Leigh syndrome (LS) is an untreatable mitochondrial disorder that leads to psychomotor regression and early death. Recently, an international research team, led by Antonio Del Sol and Alessandro Prigione, screened approved drugs to find those that could be repurposed to treat LS. They identified two strong candidates that validate the screen and that might point to therapies for LS. The findings were published in Nature Communications.
Repurposing approved drugs is an efficient method for developing new therapies, especially in the context of rare diseases. Those drugs have already been shown to be safe for use in humans. The Del Sol-Prigione team took advantage of this strategy and previous findings that implicated the SURF1 gene variants in LS. They used a brain organoid model of LS that contained SURF1 variants. The atypical progenitor organization of the organoids suggested defective neuronal morphogenesis, and the LS iPSC-derived dopaminergic neurons also showed improper features.
Using the organoids, they developed a deep learning algorithm for cell type-specific drug repurposing screening. In parallel, they used a survival screen in a yeast model of LS. Two drugs stood out in the tests. Talarozole and sertaconazole rescued neuronal morphogenesis, reduced lactate release, and improved growth in the midbrain organoids.
The results validate the use of in silico screens with human brain organoids for finding new therapies for LS and potentially other mitochondrial diseases. They also give new hope for patients with this tragic disease. This paper also complements another recent study by Dr. Prigione that was published in Cell.
Statement of Significance from Dr. Prigione
Identifying new treatment options is crucial for an incurable disease, such as LS. Here we took advantage of so-called New Approach Methodologies (NAMs), including human organoids and artificial intelligence (AI), and discovered two drugs that may be used for treating individuals with LS. This powerful platform can now be employed also in the context of other rare neurodevelopmental diseases.
A Conversation with Dr. Prigione:
MitoWorld: Can you give us an idea of the directions you might take to extend these findings?
Dr. Prigione: We are following these results on two different paths. First, we are exploring ways to bring these treatments to LS individuals. In particular, we are focusing on talarozole since it showed stronger effects in the models and has already been tested in humans as oral formulation in a trial that was conducted last year for osteoarthritis. Unfortunately, the company that developed the oral formulation for the trial did not agree to provide the drug for us. Therefore, we are looking into alternative options, including manufacturing the compound ourselves.
The second path is back to research. We are going to assess the effect of these two compounds in other LS models both humans and animals and determine their potential synergy with other drugs that we have identified, such as sildenafil (see Zink et al., Cell 2026). We are also further developing the deep learning and AI strategy to extend the computational screen to additional brain organoid models to possibly identify additional repurposable candidates and better understand the underlying mechanisms of actions in this disease context.
MitoWorld: In this paper, you focused on brain organoids. Might your overall strategy be useful with other tissues?
Dr. Prigione: Yes, combining AI and organoid models may represent a powerful approach to take advantage of NAMs and possibly reduce the reliance on animal models, especially for those disease conditions for which animal models are not available. For example, SURF1 variants cause a severe form of LS but mice without Surf1 do not show defects and even live longer than healthy animals. Therefore, human iPS models may represent an important strategy to advance drug discovery for these gene defects.
MitoWorld: You identified two potential drugs for LS. Do you plan to pursue any clinical studies to advance those treatments?
Dr. Prigione: As mentioned above, we are very much interested in exploring ways to assess these drugs (and particularly talarozole) in clinical settings. For this, we are partnering with the patient organization Cure Mito. Together, we are considering manufacturing the drug ourselves to develop an ethical path that would follow us determining the potential effectiveness of talarozole in LS individuals.
MitoWorld: You have a great strategy for repurposing drugs. On the other hand, those drugs also provide information about the disease process itself. You describe some of those implications in your Discussion.
Dr. Prigione: Yes, we speculate that drug function may be important for two aspects beyond energetics. First, they may act on retinoic acid pathway to improve neuronal development. Second, they may act on PPARγ, which may impact inflammation and was previously implicated in the positive effects seen in LS mice treated with cannabidiol (CBD). These results highlight the complexity of the disease processes and suggest that combinatorial treatment strategies might also be considered to combat both neurodevelopmental and neuroinflammatory components.
MitoWorld: We are always interested in what first interested you in mitochondria.
Dr. Prigione: During my PhD, I worked in the lab of Gino Cortopassi at UC Davis and started working on mitochondrial DNA deletions in human cellular models. That project and that experience were essential for me, as I was struck by the complexity and essentiality of mitochondria. During my postdoc, I changed the field and worked on iPS cells. Therefore, when I started my independent laboratory, I decided to combine these two topics and began using iPS models to study mitochondria-related diseases.
References
Menacho C, Okawa S, Álvarez-Merz I, Wittich A, Muñoz-Oreja M, Lisowski P, Martín ML, Pentimalli TM, Zakin S, Thevandavakkam M, Jerred C, … Del Sol A, Prigione A (2026) Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids. Nature Communications 17(1): 3570.
https://www.nature.com/articles/s41467-026-71391-2
Zink A, Dai DF, Wittich A, Henke MT, Pedrotti G, Heiduschka S, Santamaria G, Pentimalli TM, Brueser C, Notopoulou S, Umar AR, … Prigioni A (2026) Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy. Cell 189: 1656–1679.
Aging kidneys exhibit mitochondrial structural defects, oxidative stress, fibrosis, and altered metabolism. A new study published in Aging Cell suggests that alterations in the mitochondrial contact site and cristae organizing system (MICOS) may contribute to these defects.
Kidney function commonly declines with age, and aging is a major risk factor for acute and chronic kidney disease. Because many kidney cell types, especially tubular epithelial cells, have high energetic demands and rely heavily on mitochondrial function, the research team asked whether age-related changes in mitochondrial architecture contribute to this vulnerability.
Using transmission electron microscopy (TEM) and serial block-face scanning electron microscopy (SBF-SEM), the investigators examined mitochondria from the kidneys of young versus old mice. In the aged cohort, they found fragmented mitochondrial morphology, and, notably, the folds of the inner mitochondrial membrane that promote energy production, known as cristae, were disorganized, shorter, and smaller by volume. At the molecular level, aging was correlated with decreased expression of MICOS components and of OPA1, another key regulator of inner mitochondrial membrane structure.
To test whether MICOS disruption could affect mitochondrial function, the authors perturbed MICOS components in cellular models. Loss of MICOS proteins altered mitochondrial calcium handling, increased reactive oxygen species, and impaired aspects of mitochondrial respiration. Human genetic and biobank analyses further linked CHCHD6 and OPA1 with kidney and genitourinary disease phenotypes, although these findings remain associative.
Together, the study supports a model in which age-related decline of MICOS and related cristae regulators contributes to deterioration of mitochondrial inner membrane architecture. These changes are associated with oxidative stress, altered calcium regulation, metabolic remodeling, fibrosis, and increased vulnerability to kidney dysfunction during aging.
A Statement of Significance from Dr. Hinton, Jr.:
Aging is the greatest risk factor for chronic kidney disease, yet the mechanisms linking aging to renal dysfunction remain poorly understood. In this study, we demonstrate that aging is associated with profound remodeling of mitochondrial ultrastructure in the kidney, characterized by disrupted cristae architecture, altered mitochondrial morphology, increased oxidative stress, and widespread metabolic dysregulation. Using advanced three-dimensional electron microscopy, human kidney samples, large-scale biobank analyses, and mechanistic studies targeting the mitochondrial contact site and cristae organizing system (MICOS) complex, we identify age-dependent loss of MICOS components as a conserved feature of kidney aging. Furthermore, disruption of MICOS proteins directly impairs mitochondrial function, calcium handling, and redox homeostasis, recapitulating key features of the aged kidney phenotype. These findings establish MICOS complex dysfunction as a central regulator of mitochondrial structural integrity during renal aging and suggest that preserving cristae architecture may represent a therapeutic strategy to mitigate age-related kidney disease and preserve renal healthspan.
A conversation with the authors:
MitoWorld: What initially led your group to investigate the MICOS complex during kidney aging?
Hinton et. al.: This study grew from a broader question that has guided our work for many years: Does mitochondrial architecture actively influence aging, or is it simply a consequence of aging? For decades, mitochondrial dysfunction has been widely recognized as a hallmark of aging, but most studies focus on metabolism, ATP production, and oxidative stress. The primary focus was on the functional aspect, with the structural aspect given a back seat. We wanted to determine whether mitochondrial structural organization also contributes to tissue decline. This study draws the field’s attention to the role of structural organization in cellular aging.
Our laboratories had previously observed age-associated declines in MICOS proteins in skeletal and cardiac muscle, along with disrupted cristae organization, altered mitochondrial morphology, oxidative stress, and metabolic dysfunction. These recurrent observations from our lab and elsewhere suggested that MICOS decline might represent a broader biological phenomenon rather than a tissue-specific event. The kidney was compelling because it is highly energetic and densely packed with mitochondria. Even subtle changes in mitochondrial architecture could have major consequences for kidney function. Also, independent human genetic observations from our lab and Dr. Katti’s lab provided additional evidence supporting the rationale for investigating MICOS biology in renal aging.
MitoWorld: What was the major discovery of the paper?
Hinton et. al.: The major discovery was that kidney aging is accompanied by a breakdown of mitochondrial architecture, closely linked to the loss of the MICOS complex. We observed coordinated declines in MIC60, CHCHD3, CHCHD6, MIC10, MIC13, and OPA1—proteins that help maintain cristae and inner membrane organization. The key distinction from previous reports in our study is that this architectural maintenance system appears to deteriorate systematically during kidney aging.
These changes were associated with cristae disorganization, altered mitochondrial networks, oxidative stress, calcium dysregulation, fibrosis, and metabolic remodeling. Mechanistically, we propose that MICOS loss destabilizes cristae, reducing electron transport efficiency and promoting reactive oxygen species production. This may create a feed-forward cycle of mitochondrial damage. The key conceptual leap and contribution is that age-related loss of MICOS-dependent mitochondrial architecture may be a central organizing feature that links cristae disruption, mitochondrial remodeling, oxidative stress, metabolic dysfunction, and altered organelle communication in the aging kidney.
We also observed age-associated changes in mitochondria–endoplasmic reticulum contacts; the novelty here is not simply cristae disruption, but the suggestion that age-related architectural decline may influence communication between organelles.
MitoWorld: How do alterations in cristae architecture contribute to oxidative stress and mitochondrial dysfunction during aging?
Hinton et. al.: Some of the most transformative discoveries in biology emerged from the realization that structure can be a mechanism rather than merely a consequence of function. The double-helical architecture of DNA explained heredity, the quaternary structure of hemoglobin revealed cooperative oxygen transport, the organization of the sarcomere uncovered the basis of muscle contraction, and the intricate architecture of the ribosome illuminated the process of protein synthesis. In each case, biological form provided the missing causal link between molecular organization and physiological outcome.
Emerging research suggests that mitochondrial cristae follow this same pattern. Rather than treating age-associated changes in cristae morphology as a passive hallmark of mitochondrial decline, we seek to address whether alterations in cristae architecture can themselves drive functional deterioration, for example, in altered electron transport, oxidative stress, and impaired cellular and organ physiology.
Cristae organize the respiratory machinery required for oxidative phosphorylation. In aged kidneys, we observed reduced cristae volume, surface area, and integrity, accompanied by decreased MICOS expression. Disruption of cristae architecture likely impairs electron transport efficiency, increases electron leakage and reactive oxygen species production, and promotes oxidative damage. Because cristae also regulate respiratory supercomplex assembly, calcium homeostasis, and organelle communication, their deterioration may contribute broadly to mitochondrial and cellular dysfunction during aging.
MitoWorld: What advantages did 3D electron microscopy provide compared with traditional two-dimensional approaches?
Hinton et. al.: At its core, this question asks what level of observation is necessary to reveal the biological organization of aging mitochondria. A two-dimensional image can tell us what an individual mitochondrion looks like, but aging is unlikely to be an isolated organelle phenomenon. We wanted to understand how mitochondrial networks are organized throughout a tissue and how those relationships change with age. Three-dimensional electron microscopy allowed us to observe mitochondria in their native architectural context, revealing that aging may involve a loss of network organization and organelle connectivity, rather than simply damage to individual mitochondria. 3D EM allows aging to be studied as a network-level architectural process rather than as isolated mitochondrial snapshots.
Using serial block-face scanning electron microscopy, we reconstructed mitochondrial networks throughout kidney tissue. This allowed us to quantify volume, surface area, connectivity, branching, network organization, and spatial relationships with nearby organelles. A major advantage was that 3D imaging revealed network remodeling and connectivity loss that were not apparent from isolated 2D views. It also allowed us to examine how mitochondria are positioned relative to the endoplasmic reticulum, supporting our interest in the mitochondrial connectome.
MitoWorld: Do you believe MICOS proteins represent viable therapeutic targets for age-related kidney dysfunction?
Hinton et. al.: One way to think about this question is not simply whether MICOS proteins can be targeted therapeutically, but whether preserving mitochondrial architecture can preserve tissue function during aging. MICOS proteins sit at the intersection of structure and function, organizing cristae architecture, inner membrane integrity, respiratory supercomplex assembly, calcium handling, and interactions with proteins such as OPA1. This makes them particularly attractive because they may act upstream of many aging-associated processes rather than regulating a single pathway.
In our study, MICOS decline was associated with cristae deterioration, oxidative stress, metabolic remodeling, fibrosis, and kidney dysfunction. However, the critical unanswered question is whether restoring MICOS function can reverse existing pathology or merely slow its progression. Ultimately, the therapeutic promise of MICOS depends on whether mitochondrial architecture is a driver of aging or simply a marker of it.
MitoWorld: What are the most important unanswered questions regarding MICOS biology in aging tissues?
Hinton et. al.: Perhaps the most important unanswered question is not why a particular MICOS protein declines with age, but whether biological architecture itself represents a fundamental layer of aging biology. We have spent decades cataloging age-related changes in genes, proteins, and metabolites, yet cells are also highly organized spatial systems.
The emerging challenge is to determine whether aging reflects a gradual loss of this organization and whether restoring architectural integrity can restore function. Addressing that question will require us to move beyond studying individual organelles and toward understanding the cellular connectome—the network of interactions that links mitochondria with the ER, lysosomes, lipid droplets, and other compartments. In that sense, the future of the field may be less about mitochondria themselves and more about how cellular architecture is maintained across the lifespan.
Looking ahead, we believe the most exciting aspect of this work is not what it answers, but what it leaves unanswered. In our opinion, the following questions will be particularly important in the years ahead, as they address the fundamental relationship between mitochondrial architecture, cellular organization, and aging.
- What drives the age-dependent decline of the MICOS complex?
- Can restoration of MICOS reverse age-associated dysfunction?
- How does MICOS shape communication between mitochondria and the rest of the cell?
MitoWorld: What are the major limitations of the study?
Hinton et. al.: Every study ultimately comes down to the difference between what we can observe and what we can conclude. Scientific progress often occurs in two stages: first, identifying a pattern, and then proving that the pattern is causal. This study provides strong evidence that MICOS decline and architectural remodeling accompany kidney aging, but the ultimate test will be determining whether restoring that architecture can meaningfully alter the aging process itself.
Reference:
Fatigue and Primary Mitochondrial Disease
Mitochondria have long been associated with the production of cellular energy. Thus, it is not surprising that patients with primary mitochondrial disease experience debilitating fatigue. In a paper in Molecular Genetics and Metabolism, a multi-institute research team led by Amel Karaa at Harvard Medical School studied the relationship between primary mitochondrial disease and fatigue. They developed a brief report that patients can use to track their disease and improve treatments in clinical trials. Thus, this tool can make future trials more rigorous and relevant to the people they aim to help.
Clifford S, Stefanetti RJ, Bahar R, Hansson MJ, Gorman GS, Karaa A (2025) Qualitative study of fatigue in adults with primary mitochondrial disease: Development of the PROMIS Fatigue Mitochondrial Disease Short Form. Molecular Genetics and Metabolism 145(4): 109153.
Mitochondria and Cell Death Signaling
Mitochondria are well known for their role in energy production, but they are so much more. In an excellent recent review in Current Opinion in Cell Biology, Ella Hall-Younger and Stephen WG Tait describe the state of research into the involvement of mitochondria in apoptotic signaling. Mitochondria are a sort of signaling hub for the many types of programmed cell death. With only a few genes, mitochondria have assumed many roles, and one of the most critical is programmed cell death. This review is an excellent summary of the current state of knowledge of those issues.
Hall-Younger E, Tait SW (2025) Mitochondria and cell death signaling. Current Opinion in Cell Biology 94: 102510.
Preventing Mitochondrial Diseases with Donated Mitochondria
A multi-institute research team developed a procedure to prevent mitochondrial disease in fetuses by using donated mitochondria. The team was led by Doug McFarlane and Louise A. Hyslop. Preimplantation genetic testing can identify embryos with low levels of variants. In mitochondrial donation, microsurgery is used to transplant the nuclear genome from an egg of a woman with the mtDNA variant to an enucleated egg from an unaffected woman. Permission to use this procedure required an act of Parliament in the United Kingdom. Still, this is a solid breakthrough for women who want to reduce the risk of passing on mitochondrial diseases to their offspring.
Hyslop LA, Blakely EL, Aushev M, Marley J, Takeda Y, Pyle A, Moody E, Feeney C, Dutton J, Shaw C, Smith SJ (2025) Mitochondrial donation and preimplantation genetic testing for mtDNA disease. New England Journal of Medicine 393: 438-449.
A multi-institute research team, led by Prof. José Pedro Friedmann Angeli, examined the activity of ferroptosis suppressor protein 1 (FSP1) in protecting against phospholipid peroxidation and ferroptosis. They discovered that riboflavin is a critical mediator for stabilizing FSP1 and suggest riboflavin metabolism as an intriguing possible therapeutic strategy. The findings were published in a recent paper in the journal Nature Cell Biology.
Membranes are critical elements of all cells, but they can be damaged by oxidation. Damaged membranes can activate the programmed cell death mechanism known as ferroptosis. Ferroptosis is carefully regulated, and one of the key regulators of that process is the protein FSP1. Membrane damage and ferroptosis are often observed in cancer, neurodegenerative diseases, and ischemia-reperfusion injuries.
Prompted by this information, the Friedmann Angeli team sought to identify factors that regulate FSP1 function. They used a CRISPR-Cas9 screen to find such factors. Interestingly, the screen discovered that riboflavin has a role in maintaining the stability of FSP1 and, thus, modulates membrane phospholipid peroxidation and ferroptosis. In addition, they found that roseoflavin, an antimetabolite of riboflavin, interferes with FSP1 function and, thus renders cancer cells susceptible to ferroptosis.
These findings increase our understanding of how membranes are maintained and also have intriguing clinical implications. Using riboflavin to modulate FSP1 activity might provide therapeutic strategies for treating cancers and neurodegenerative diseases.
Statement of Significance: Vera Skafar
Riboflavin is an essential nutrient obtained from the diet and converted inside cells into molecules that support numerous metabolic reactions, including those that protect against oxidative damage. We found that riboflavin deficiency makes cancer cells highly susceptible to ferroptosis by compromising the FSP1 protective axis. Our findings uncover a link between a common nutrient and a key survival mechanism in cancer cells, offering a new strategy to trigger ferroptosis and potentially enhance anticancer therapies. The paper shows that interfering with metabolization of riboflavin (for example, using antimetabolites, such as riboflavin) can sensitize cancer cells to ferroptosis, revealing a metabolic vulnerability. Importantly, these observations have been validated across multiple cancer cellular models, including high-FSP1-expressing melanoma, breast and lung cancer cell lines. Beyond cancer, this mechanism is also relevant to diseases involving oxidative stress and ferroptosis, including neurodegenerative disorders and ischemia-reperfusion injury.
A Conversation with Vera Skafar:
MitoWorld: This is an interesting finding. Could you indicate what the next steps in your research might be?
Vera Skafar: Building on the molecular mechanisms established in this study, we’re now moving toward the translational edge of our research to explore the therapeutic potential of these insights. We’re focused on identifying and developing small-molecule inhibitors of riboflavin metabolism and assessing whether they can induce ferroptosis in preclinical cancer models.
MitoWorld: Riboflavin-derived metabolites are important in mitochondrial function, which is implicated in cancer and neurodegenerative diseases. Can you describe how your findings with riboflavin and FSP1 might be relevant to mitochondria health?
Vera Skafar: We believe our findings are relevant to the MitoWorld community because riboflavin metabolism strongly influences mitochondrial function. Under deficiency, we observe a clear downregulation of mitochondrial activity. This is especially interesting in the context of cancer, where increased mitochondrial function has been linked to therapy resistance and the ability of tumors to adapt to stressful environments, such as acidic conditions. In that sense, interfering with these pathways could represent a strategy to limit mitochondrial-driven resistance mechanisms and potentially improve existing cancer therapies.
MitoWorld: Interestingly, you note the importance of selenium, as well as riboflavin, to modulation of ferroptosis and suggest that micronutrients are critical to the health of membranes. Are you looking for other factors that influence membranes?
Vera Skafar: Absolutely. What’s becoming clear is that membrane health depends on a network of metabolic inputs. Selenium supports GPX4, riboflavin supports FSP1, and together they form complementary defense systems. We’re now looking more broadly at other vitamins, cofactors, and lipid metabolic pathways that might influence ferroptosis sensitivity. It’s an exciting area connecting nutrition, metabolism, and cell death.
MitoWorld: The results with riboflavin are interesting. Can you see that as part of a therapy?
Vera Skafar: The FSP1 protective axis is important for certain cancers, such as lung adenocarcinoma, and riboflavin metabolism has been reported to represent a metabolic dependency in hematological malignancies (myeloid and lymphoid), as well as in pancreatic ductal adenocarcinoma. Targeting the metabolization of riboflavin could therefore open new treatment opportunities, especially in combination with existing targeted therapies, where we’re seeing a synergic effect. Importantly, emerging evidence suggests there could be a therapeutic window where cancer cells are vulnerable, but healthy tissues are largely unaffected, making this approach particularly promising.
MitoWorld: Riboflavin is a common vitamin. Can you imagine ways that it might be harnessed to treat the diseases involving membrane damage and ferroptosis?
Vera Skafar: It really depends on the disease context. In conditions such as neurodegeneration, supporting riboflavin-dependent pathways could help protect membranes from oxidative damage. However, in cancer those same pathways can help malignant cells survive, so inhibiting riboflavin metabolism might be beneficial. Our findings may also help explain why riboflavin supplementation studies in cancer have shown inconsistent results, highlighting the need for caution when boosting these pathways.
Reference
Skafar V, de Souza I, Ghosh B, Ferreira dos Santos A, Porto Freitas F, Chen Z, Sun S, Donate Castillo M, Nepachalovich P, Seufert L, Bothe S, et al. (2026) Riboflavin metabolism shapes FSP1-driven ferroptosis resistance. Nature Cell Biology 13: 1-1. doi: 10.1038/s41556-025-01856-x
A multi-institute research team, led by Arupratan Das, sought to find possible drugs to treat glaucoma. Using a high throughput mitochondrial screen in retinal ganglion cells (RGCs), they identified the 5-HT1A antagonist WAY-100635 (WAY) as an intriguing candidate. The paper was published in a recent issue of the journal Communications Medicine.
Early metabolic dysfunctions in RGCs have been implicated in glaucoma. Moreover, mitochondrial abnormalities cause degeneration of RGCs and have been implicated in mitochondrial optic neuropathies (MON), such as Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA).
Unfortunately, there is no approved therapy for preserving vision in this disorder. The Das research team set out to solve this problem. They used a live-cell mitochondrial screen in human embryonic stem cell-derived retinal ganglion cells. They identified the 5-HT1A antagonist WAY-100635 (WAY) as a candidate. WAY restored mitochondrial fitness, inhibited excitotoxicity, and enhanced aerobic glycolysis. It also preserved visual acuity and stopped glaucoma progression of the disease in mouse models of glaucoma mice. Importantly, WAY has already been approved for other indications, and not surprisingly, it showed no toxicity in the models used in this study.
The findings of this study are significant. No approved therapy is currently available for treating glaucoma. Here, the authors identified WAY as an intriguing possible treatment for this debilitating disorder. The results will give new hope to patients with glaucoma and other mitochondrial optic disorders.
A Statement of Significance from Dr. Das:
Glaucoma causes irreversible blindness by damaging retinal ganglion cells (RGCs), the neurons that carry visual information from the eye to the brain. Today’s treatments mainly lower eye pressure, yet many patients still lose vision because no approved therapy directly protects these neurons or preserves the retina-to-brain visual circuit. In this study, we used a live-cell screen in human stem cell–derived RGCs to identify a small molecule that strengthens cell’s energy producing unit mitochondria and protects these neurons. We show that it boosts key survival signaling, restores mitochondrial function, and preserves visual pathway activity in animal models. A major translational advantage is that this compound has already been used in human brain-imaging clinical studies, providing an existing safety foundation that could accelerate development of a first-in-class neuroprotective add-on therapy for glaucoma and potentially other optic nerve diseases.
A Conversation with Dr. Das:
MitoWorld: What are your plans to continue this line of research?
Dr. Das: This publication is the starting point for a much broader research program. Next, we want to determine which retinal ganglion cell (RGC) subtypes are protected; because different RGC classes support distinct visual functions (light/dark sensitivity, motion detection, and image-forming vs. non–image-forming vision). In parallel, we will deepen the molecular mechanism in human stem cell-derived RGCs by mapping the full downstream signaling network triggered by 5-HT1A antagonism, how cyclic adenosine monophosphate (cAMP) dynamics, PGC-1α–linked mitochondrial biogenesis, and mitochondria independent signaling converge to prevent degeneration. We will also define the metabolic reprogramming in the native retina, asking how the treatment reshapes energy use across compartments (RGC soma vs. long axons in the optic nerve), and whether this involves coupling mitochondria to aerobic glycolysis to sustain axonal structure and transport. Finally, we will test whether protection is purely RGC-autonomous or also involves neighboring retinal neurons, glia, and immune cells, and we will rigorously distinguish axon preservation from true axon regrowth with longitudinal tracing and optic-nerve profiling.
MitoWorld: Can you expand on the mechanisms for how WAY seems to protect the RGCs?
Dr. Das: In our study, we show that WAY acts by antagonizing the 5-HT1A G-protein–coupled receptor (GPCR), which reversibly elevates cyclic adenosine monophosphate (cAMP) in retinal ganglion cells. cAMP is a central second messenger that coordinates multiple neuroprotective programs, and in our system, it restores mitochondrial health in part by transiently activating PGC-1α–dependent mitochondrial biogenesis. Improving mitochondrial fitness showed two key consequences: it reduced the metabolic “workload” per mitochondrion (lowering stress while sustaining energy supply), and it supported a protective metabolic state that couples mitochondria with aerobic glycolysis. That glycolytic program is not just an ATP backup; it supplies building blocks needed for protein and lipid synthesis that help RGCs survive and maintain long-distance axonal structure and function.
MitoWorld: Your study was predicated on finding possible therapies for glaucoma. Do you have plans to take WAY into clinical trials?
Dr. Das: Yes, we are actively planning an FDA-enabling path and are serious about advancing WAY toward a first-in-human trial. Our next goal is to generate a complete Good Laboratory Practice (GLP) preclinical toxicology and pharmacokinetic data package using GLP-manufactured WAY, including dose-ranging, safety margins, and exposure–response relationships in a higher model (for example, canine), to support an Investigational New Drug (IND) application and a Phase I clinical trial. In parallel, we are optimizing drug formulation and delivery to maximize bioavailability and real-world usability, prioritizing an oral regimen and a long-acting depot option (for example, poly(lactic-co-glycolic acid) (PLGA) slow-release packaging for intramuscular administration) that could be practical across different patient age groups. We are also actively seeking funding to execute these critical translational studies because we believe this program represents a real opportunity to deliver a neuroprotective therapy for glaucoma, and potentially other optic neuropathies, where current treatment options remain limited to pressure management.
MitoWorld: You note that these findings might benefit studies of other neurodegenerative diseases. Can you elaborate on how that might work?
Dr. Das: The reason we believe these findings can extend beyond glaucoma is that WAY targets a core, convergent stress pathway that many neurodegenerative conditions share -loss of metabolic resilience, and mitochondrial stress. We are already testing this directly in traumatic brain injury (TBI) models and are seeing strong, reproducible early signals: TBI triggers progressive degeneration of retinal ganglion cells and robust immune activation in injured brain regions, whereas following injury WAY treatment preserves retinal ganglion cell survival, markedly reduces neuroinflammatory responses in the lesion, and is associated with improved visual function (including visual acuity) and reduced anxiety-like behavior. We are currently completing the remaining validation experiments and preparing this dataset for submission, with the broader goal of defining where this mechanism provides the greater therapeutic leverage across optic neuropathies and related brain-injury conditions.
MitoWorld: You mention that, in some glaucoma models, intraocular pressure disrupts mitochondrial function. Do you have any idea of how that happens?
Dr. Das: Yes. In glaucoma, high eye pressure puts the greatest strain on the point where retinal ganglion cell axons leave the eye, the optic nerve head. These axons are still unmyelinated there and they make a sharp turn as they enter the nerve, which makes this region mechanically and energetically demanding. Under pressure stress, axonal transport slows down, so mitochondria and other cargo can pile up in the optic nerve head. Because unmyelinated axons already rely heavily on mitochondria for energy, this added crowding and stress can increase harmful mitochondrial byproducts and damage the mitochondria, making the retinal ganglion cells more vulnerable over time.
MitoWorld: Are you surprised by the rapidly growing recognition of the importance of mitochondria in human disease?
Dr. Das: I’m not surprised. Life ultimately runs on energy, and mitochondria sit at the center of how cells make and manage that energy. Across many diseases, we now see mitochondrial metabolism and quality control become disrupted; sometimes as an early contributor and sometimes as a downstream consequence. Either way, if we learn how to restore mitochondrial fitness in a cell- and disease-specific manner, we can open new therapeutic options by addressing root vulnerabilities or by buffering the harmful cascades that follow.
Reference
Dutta S, Surma ML, Chen J, Anbarasu K, Meng J, Want N, Das A (2026) The 5-HT1A receptor antagonist WAY-100635 maleate promotes retinal ganglion cell differentiation and protects the retino-visual circuits. Commun Med 6: 254.
A screen of iPS cells recently identified sildenafil as a potential treatment for Leigh syndrome (LS). Moreover, further testing of the drug showed marked improvement in animal models and human patients. The results of the study, led by Alessandro Prigione, were published in Cell.
LS is a severe mitochondrial disease that affects neurological development and muscles and results in death. It is caused by mutations in over 100 genes in either the nuclear or mitochondrial genomes. There are no treatments. Moreover, the lack of model systems has been a major obstacle to understanding LS.
The Prigione research team set out to change this. They used iPS cells from LS patients to generate neural precursor cells (NPCs). Those cells have an MT-ATP6 variant with abnormal mitochondrial membrane potential that can be exploited in screens. They screened 5,632 approved compounds and identified sildenafil as a possible candidate.
Sildenafil has been implicated in the treatment of multiple disorders. It is widely studied and beneficial in a wide range of conditions, including pulmonary arterial hypertension in children. In this study, it relieved disease symptoms, promoted neuronal outgrowth, normalized calcium homeostasis in human and animal models of LS and in six patients treated on individual basis.
The findings in this study demonstrated the value of screenings in iPS cell models and also identified sildenafil as a potential therapy for mitochondrial diseases. Dr. Prigione recently published a separate study that complements this one. That study in Nature Communications is the subject of a separate blog.
A Statement of Significance from Dr. Prigione:
LS is currently untreatable. The most frequent causes are variants in the mitochondrial gene MT-ATP6. Since it is difficult to engineer mitochondrial DNA (the famous genetic scissor CRISPR does not work for the mitochondrial DNA), it has been difficult to study this disease. Using patient-derived neural cells, we could screen drugs directly in the cell type affected by the disease. We identified sildenafil as a promising drug. We performed several validations using 3D organoid models and also animal models of LS due to nuclear genetic variants. Since sildenafil can be safely used in children with pulmonary arterial hypertension, we could treat children with LS on off-label individual basis. Sildenafil improved motor and developmental function and lowered the risk of metabolic crises, which can be detrimental in affected individuals. A double-blind placebo-controlled trial is now being set up to start in October 2026.
A Conversation with Dr. Prigione and Dr. Annika Zink, first author of the study in Cell
MitoWorld: You have developed a new method for repurposing existing drugs. Do you have plans for continuing this line of research?
Dr. Zink: Definitely. We are currently using iPS models in 2D and 3D to study additional treatments for LS and other rare disorders. The bottleneck is finding a reliable disease phenotype in these models. Once this is identified, we can use the models as drug discovery platform. In fact, in an AFM-funded project, we are employing our iPS platform not only for repurposable drugs but also to assess complementary strategies based on gene therapy.
Dr. Prigione: We have a new consortium called SynLeigh that starts in June 2026 and is funded by the European rare disease program ERDERA. In this project, we are looking at potential synergy of sildenafil with other repurposable drugs to find improved therapeutic options. We are also investigating the impact of sildenafil on different variants causing LS and in the context of other mitochondrial disorders.
MitoWorld: Do you think the iPS cells could be used in other tissues and diseases?
Dr. Zink: Yes. This is the strength of this model. iPS cells can be easily differentiated into different cell types and tissues in both 2D and 3D. Patient-specific iPS models make it possible to study tissue-specific disease mechanisms and also provide a powerful platform for disease modeling and drug discovery. In fact, in our study in Cell, we used cardiac cells generated from LS patient iPS cells to exclude potential cardiotoxicity of sildenafil.
Dr. Prigione: In our laboratory, we are using iPS cells to generate different types of brain organoids (e.g., cortex, cerebellum, midbrain). These studies may help us to understand which areas of the brain can be more strongly impacted by disease features. In this way, we may discover underlying mechanisms that could be targeted for therapies.
MitoWorld: Sildenafil has shown promise in a surprising number of different disorders. Can you speculate on why that is so? Is it due to its connection to calcium and mitochondria or simply vasodilation?
Dr. Prigione: This is exciting. Previous works suggested that sildenafil may be beneficial also in Alzheimer’s disease or Huntington’s disease. We like to think that it has to do with the central role of mitochondria in several disease processes. If sildenafil can improve mitochondrial calcium and increases the delivery of oxygen to tissues, it may provide support in those conditions that could benefit from additional energy. Surprisingly, lower oxygen has also been found beneficial in LS. Perhaps then the modulation of oxygen is really crucial, and additional work should focus on understanding this aspect.
MitoWorld: Are you interested in taking sildenafil into clinical trials for the mitochondrial diseases?
Dr. Prigione: Yes, we are currently setting up a randomized double-blind placebo-controlled trial with sildenafil in individuals with LS carrying MT-ATP6 variants. We should start recruiting patients in October 2026. We designed the trial in concert with the European Medicines Agency (EMA). To achieve a sufficient patient number, the trial will be conducted in Germany, The Netherlands, France, Italy, and Spain. We welcome patients coming from additional countries if their conditions allow them to travel to one of the trial sites.
Unfortunately, no pharma showed any interest in financial supporting this. The trial is entirely supported by third-party funding, primarily through the Horizon consortium SIMPATHIC (www.simpathic.eu). In fact, we are searching for additional funds to cover greater expenses due to the larger number of patients requested by EMA. We would be grateful if anyone would like to reach out for suggestions on how to raise additional funds. For patient families interested in the trial, please write to this email address: Simpathic.aig@radboudumc.nl
MitoWorld: We asked you about your interest in mitochondria in another blog. Interest has grown in mitochondria in various diseases. What is your sense of where all this research is going?
Dr. Prigione: Mitochondria are increasingly recognized in aging and several disease processes and also as treatment targets. Improving mitochondrial function may be seen in the future as a central goal for several therapeutics and as a general strategy to maintain health and prevent deterioration. Transplantation of mitochondria may also represent an innovative approach beyond compounds and gene therapy applications. As rare disease researchers, we hope that this renewed interest in mitochondria in more common conditions would lead to increased treatment options for children affected by primary mitochondrial diseases.
References
Zink A, Dai DF, Wittich A, Henke MT, Pedrotti G, Heiduschka S, Santamaria G, Pentimalli TM, Brueser C, Notopoulou S, Umar AR, … Prigioni A (2026) Pluripotent stem-cell-based screening uncovers sildenafil as a mitochondrial disease therapy. Cell 189: 1656–1679.
https://www.cell.com/cell/fulltext/S0092-8674(26)00173-X
Menacho C, Okawa S, Álvarez-Merz I, Wittich A, Muñoz-Oreja M, Lisowski P, Martín ML, Pentimalli TM, Zakin S, Thevandavakkam M, Jerred C, … Del Sol A, Prigione A (2026) Accelerating Leigh syndrome drug discovery through deep learning screening in brain organoids. Nature Communications 17(1): 3570.
“There is a lot we can learn from putting together the mitochondria and cancer research fields, from a better understanding of basic biological processes to identifying metabolic vulnerabilities with clinical potential. I am particularly looking forward to seeing how the Mitochondria-Cancer Atlas Working Group will provide a higher resolution into mitochondrial function across cancer types and how it can be leveraged therapeutically.” Salvatore Fabbiano, PhD, Editor-in-Chief, Cell Metabolism
Cancer cells lead a harsh existence. To support their growth, they need large amounts of energy, but their environment involves hypoxia, metabolic competition, and nutrient scarcity. Interestingly, they manipulate that environment and particularly their mitochondria to mitigate those challenges.
Cancer presents a unique opportunity to understand how tumors manipulate mitochondria and to ask what those lessons mean both for the cancer community and mitochondrial biology. A commentary in Cell Metabolism by Thomas MacVicar, Laura Greaves, Payam Gammage, and Stephen Tait of Cancer Research UK Scotland Institute, Kelsey Fisher-Wellman of Wake Forest University and MitoWorld’s Gordon Freedman expands on this insightful observation. The intersection of these two research fields has informed studies of metabolic reprogramming, mitochondrial genetics, and regulation of cell death.
The metabolic reprogramming of mitochondria is critical to cancer cells. For example, the accumulation of oncometabolites due to mutations drive cancers in distinct cell types. One of the more intriguing aspects of mitochondria is their ability to migrate from cell to cell to enhance tumor metabolism or to weaken immune cell defenses. As more is learned about changes in mitochondrial metabolism, the challenge becomes of how to translate these advances into possible new biomarkers and therapeutic strategies for the treatment of various cancers.
Mitochondria have their own small genome, and mutations in mitochondrial DNA (mtDNA) are widespread across tumor types but non-random. While the role of these mutations in cancer is not clear, mutation burden, heteroplasmy, copy number, and other factors may be involved. Normal age-related mutations seem to accumulate in tumors, and some others may be subject to selective pressures during tumor evolution. These features of mtDNA may have potential as biomarkers and therapeutic targets, and in turn, advances in cancer biology will elucidate principles of mitochondrial genetics.
Although mitochondria are best known for producing cellular energy, they also have a significant role in programmed cell death. In apoptosis, the mitochondrial outer membrane becomes permeable and release proteins that activate caspases. Tumors can circumvent this cascade of activities. Yet, this very weakness suggests a possible therapy by inhibiting caspases and encouraging anti-tumor immunity.
In the last few years, scientists and physicians have come to realize that mitochondria do so much more than simply transform cellular energy. They have fundamental roles in a wide variety of human diseases, such as cancer. However, the activities of cancer cells provide a means to study mitochondria and, in turn, elucidate the biology of cancer. This strategy might be particularly helpful in “threading the needle” to kill cancer cells while leaving normal cells untouched. The metabolic reprogramming, mtDNA mutations, or openings in programmed cell death offer new possibilities for treatments. One hopeful development by the authors and others has been the establishment of the Mitochondria-Cancer Atlas Working Group. They hope to use modern molecular methods to define quantitative measurements of mitochondrial physiology and apply those findings to cancer biology and treatments. Although cancer is the initial focus, those same processes will eventually be applied to the many other diseases associated with mitochondria.
“Mitochondria are intimately involved in so many aspects of our health,” said Gordon Freedman. “Our goal here is to leverage our knowledge of cancer and mitochondria to improve human health.”
A Conversation with the Authors.
MitoWorld: The Cell Press Symposium on “Multifaceted Mitochondria” will emphasize the close relationship between cancers and mitochondria. What are you looking forward to from that meeting?
MacVicar: The roundtable session dedicated to mitochondria in cancer will be a nice opportunity to discuss new ideas for characterizing mitochondrial signatures in tumors and identifying disease-specific metabolic vulnerabilities.
Greaves: I am particularly looking forward to the round-table discussion. It will be exciting to hear different perspectives from researchers working in cancer, mitochondrial disease, and basic mitochondrial research, and to explore where these fields overlap.
Fisher-Wellman: The conference will bring together experts in mitochondrial biology across multiple disciplines. This kind of interdisciplinary environment is often the best catalyst for new ideas and impactful collaborations.
MitoWorld: Your commentary describes three general areas of intersection between mitochondria and cancers. Is there one area that you think will yield patient benefit sooner than the others?
MacVicar: Metabolic reprogramming, mitochondrial genetics and cell death signaling are interconnected. Unveiling the interactions between these mechanisms will improve our chances of targeting mitochondria effectively in future cancer treatments.
Fisher-Wellman: Because all therapies must achieve a therapeutic window, I am bullish on leveraging the intrinsic biology of tumor cells to drive cancer-type–specific targeting. The success of CLPP activators is a strong example. Once specificity was achieved (CLPP is highly expressed in the indicated cancers relative to most all other tissues of the body), durable responses can follow.
Greaves: I think mitochondrial signaling and its role in cancer therapy resistance may be the fastest route to patient benefit. While targeting cancer metabolism is an attractive approach, I think we need to be cautious, given the potential for toxicity in healthy tissues. Understanding how mitochondrial function influences treatment response in specific cancer contexts may offer more selective ways to improve existing therapies and ultimately benefit patients.
MitoWorld: What has surprised you the most in your studies of cancer and mitochondria?
MacVicar: Coming from a background of studying mitochondria in cultured cell lines, I continue to be amazed by the metabolic crosstalk between cancer cells, immune cells and stromal cells within primary and metastatic tumor microenvironments.
Fisher-Wellman: The remarkable specialization that exists within and across cancers. They are certainly not all organized the same, and this creates a massive opportunity.
Greaves: What has struck me most is the extent of tissue specificity in mitochondrial function across cancers. While not entirely surprising given my background in ageing and mitochondrial disease, it has important implications for therapeutic development.
MitoWorld: Although mitochondrial exchanges between cells was controversial just a few years ago, it now seems to be real. Can you elaborate on how that feature might be leveraged in cancer biology?
Fisher-Wellman: Understanding how these transfer events reshape cancer cell biology and the surrounding immune microenvironment is an exciting area of exploration.
MitoWorld: Can you describe the work of the Mitochondria-Cancer Atlas Working Group and what you hope it will achieve?
Fisher-Wellman: Early efforts to target mitochondria in cancer were heavily skewed toward core energy transduction pathways that are ubiquitous across tissues. While this approach has not translated into clear clinical benefit, it has been informative. The key lesson is that mitochondria themselves are not drug targets per se; rather, the tissue- and context-specific biology encoded within them is actionable. The goal of the Atlas is to systematically define this specialized biology across cancer types, with the aim of enabling truly cancer-specific mitochondrial targeting strategies.
Greaves: I hope that by mapping mitochondrial biology across different cancers, we can gain a better understanding of tissue-specific mitochondrial dependencies and uncover new opportunities for therapy.
Freedman: MitoWorld became interested in cancer and mitochondria to help put definition around the mitochondria transfer question that is debated in the mitochondrial research community. It seemed that cancer provided an incredible long-term laboratory for what can be done to and with mitochondria. Once we examined this, it seemed an atlas of mitochondrial variation by cancer and tumor state would be useful, and we met up with Fisher-Wellman to organize a working group.
MitoWorld: What is your sense of how other researchers and clinicians are picking up on the association of mitochondria with cancer and other diseases?
Freedman: MitoWorld posted a MitoBlog about the mitochondria transfer session, Mitochondrial Transfer Networks in Cancer Progression, at this year’s American Association of Cancer Research. This was one of the first mitochondria sessions at a major cancer conference, and there was standing room only.
Fisher-Wellman: The idea that organelle biology is central to many aspects of cancer cell function is becoming hard to ignore. That said, it is still underappreciated just how different mitochondria are in their intrinsic biology. Mapping this specialization is critical for scaling mitochondrial-targeted therapies that can meaningfully translate to the clinic.
This will be great to learn more about at the MitoWorld roundtable session!
Reference
MacVicar T, Greaves LC, Gammage PA, Tait SWG, Fisher-Wellman KH, Freedman G (2026) Cancer as a window into mitochondrial biology. Cell Metabolism. In press.
In a recent study by Dr. Ana Andreazza of The University of Toronto, a team of researchers generated 3D brain organoids from patient blood cells to study how cells from patients with bipolar disorder differed from those without. Culturing these brain organoids from 3 normal controls and 3 patients with bipolar disorder (BD), they find significant metabolic and immune differences that impact neuronal function. The study published in Translational Psychiatry points to mitochondria as key players in this complex psychiatric condition.
Comparing BD-derived brain organoids to normal controls, Andreazza finds many abnormalities. While their structure, organization and cell types are normal (consisting of neurons and astrocytes), their metabolic function is impaired. Deficits in ATP within these cells can be traced back to dysfunctional mitochondria, which exhibit altered morphology and weaker membrane potentials. BD brain organoids have small, rounded mitochondria, indicative of immature organelles experiencing oxidative stress and fragmentation. Indeed, these mitochondria show deficits in membrane potential and polarization, which are essential to generate ATP. As a result, these cells are not able to keep up with the high energy demands of neurons in the brain, leading to misfiring and hyperactive neural networks that are a hallmark of BD. This energy deficit also impairs neurogenesis, with BD brain organoids containing fewer cells than controls.
Not only do dysfunctional mitochondria impact brain function via energy deficits, but they also drive a neuroinflammatory cascade that further damages neurons. When mitochondria are stressed they release reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) into the cell, both of which are elevated in the BD brain organoids compared to controls. These molecules trigger innate inflammatory pathways, including inflammasome activation, that drive neuroinflammation and pathology in a self-reinforcing cycle. These impacts are observed in neurons and astrocytes, supporting cells that promote neuronal health but can perpetuate inflammatory damage when dysregulated.
Many of Andreazza’s findings in brain organoids parallel observations in patients with BD. For example, high ROS and mtDNA are associated with symptom severity in patients. As such, she attempts to correct some of these abnormalities with molecules that block inflammasome activation. Applying the inflammasome inhibitor MCC950 normalizes inflammasome activity in BD brain organoids and also reduces mtDNA release, indicating a reduction in mitochondrial stress. However, phase II studies of MCC950 for the treatment of autoinflammatory and autoimmune disorders suggest it may cause liver toxicity, so Andreazza also tested a new compound: Bioactive Flavonoid Extract (BFE), which has antioxidant, anti-inflammatory and neuroprotective effects via partial inflammasome inhibition. While inflammasome inhibition was not as strong with BFE, it did reduce mtDNA release to a similar extent. There may be opportunities for elevating the dose or combining it with other treatments to achieve greater impacts.
Altogether Andreazza’s study deconstructs molecular and cellular mechanisms at the intersection of metabolic and immune dysregulation in bipolar disorder. With the novel patient-derived 3D brain organoid model, she aims to bridge the gap between molecular pathology and clinical interventions.
Statement of Significance from Dr. Andreazza:
This study provides a patient-derived, human brain model that links mitochondrial dysfunction, inflammasome activation, and abnormal neuronal activity in bipolar disorder. Led by first author Dana El Soufi El Sabbagh, our team generated cerebral organoids from induced pluripotent stem cells derived from individuals with bipolar disorder and matched controls. The bipolar disorder organoids showed reduced ATP production, altered mitochondrial morphology and membrane potential, increased release of reactive oxygen species and cell-free mitochondrial DNA, and heightened NLRP3 inflammasome sensitivity, accompanied by hyperactive neuronal firing. Importantly, pharmacological inhibition of NLRP3 and a bioactive flavonoid extract partially restored cellular homeostasis, supporting the mitochondria-inflammasome axis as a tractable therapeutic pathway. This work was made possible through a close partnership with Australian collaborators at Deakin University, IMPACT and Barwon Health, who enabled patient recruitment and sample preparation. We are especially grateful to the patients and controls whose participation made this research possible.
A Conversation with Dr. Andreazza:
MitoWorld: Do you have an idea or theory on how mitochondrial dysfunction may play a role in the flip between manic and depressive episodes in bipolar disorder? Are the mitochondria acting differently in these different circumstances?
Dr. Adreazza: Our study did not directly compare cells from manic versus depressive states, so I would be cautious about assigning a specific mitochondrial profile to each episode. What we can say is that mitochondria sit at the centre of processes that are highly relevant to mood-state transitions: ATP production, calcium buffering, oxidative stress, inflammatory signalling, and neuronal excitability. One working model is that an intrinsic mitochondrial vulnerability reduces the energetic flexibility of neurons and astrocytes. During periods of high demand, such as sleep disruption, psychosocial stress, or systemic inflammation, cells may compensate by increasing excitability and stress signalling. This could contribute to manic symptoms in some contexts. Over time, the same system may become energetically depleted, inflammatory pathways may remain activated, and neuronal networks may lose resilience, contributing to depressive symptoms. Rather than mitochondria being entirely different organelles in mania and depression, I think their function may shift dynamically across a spectrum of energetic compensation, oxidative stress, and inflammatory burden.
MitoWorld: Bipolar disorder, and many other psychological conditions where mitochondria are implicated, arise during late adolescence and early adulthood. Do you expect this is when the mitochondria start dysfunctioning, or have they been dysfunctioning all along and reach a certain threshold around this time? Why now?
Dr. Adreazza: I suspect that, in many individuals, mitochondrial vulnerability is present before the first clinical episode, but it may not become functionally limiting until the brain reaches a developmental and environmental threshold. Late adolescence and early adulthood are periods of intense synaptic refinement, circuit maturation, hormonal change, circadian instability, increased psychosocial stress, and, for many people, changes in sleep, diet, and substance exposure. All of these factors place substantial demands on mitochondrial metabolism and redox regulation. If mitochondrial reserve capacity is already reduced, the system may tolerate early development but become less able to adapt when neuronal circuits require more precise energy regulation. Our cerebral organoid data support the idea of an intrinsic, patient-derived cellular vulnerability, because the mitochondrial, inflammatory, and electrophysiological phenotypes emerged in vitro. However, clinical illness likely reflects the interaction between this vulnerability and developmental timing, genetic background, medications, lifestyle, immune activation, and environmental exposures.
MitoWorld: The use of therapeutics to target the inflammasome in your study sounds promising… what are the next steps for potential treatments along those lines? Are there other therapies targeting mitochondria directly that have been tried? What are the challenges to this approach?
Dr. Adreazza: The next step is replication and refinement. We need to test a larger and more clinically diverse set of patient-derived organoids, define dose-response and timing effects, and determine whether inflammasome modulation improves not only inflammatory markers, but also mitochondrial function and neuronal activity. MCC950 was useful experimentally because it is a selective NLRP3 inhibitor, but concerns about hepatotoxicity make it less straightforward as a clinical path. This is why compounds such as the bioactive flavonoid extract are interesting: they may provide broader antioxidant and anti-inflammatory effects, although their potency, active components, pharmacokinetics, safety, and ability to reach the brain need careful evaluation. Mitochondria-directed strategies have also been explored in mood disorders, including agents that influence oxidative stress, bioenergetics, and mitochondrial resilience, such as N-acetylcysteine, coenzyme Q10, creatine, and the mitochondrial effects of lithium. The challenge is that mitochondria are essential in every tissue, and bipolar disorder is biologically heterogeneous. We will need biomarkers to identify who has a mitochondria-inflammatory phenotype and to monitor target engagement.
MitoWorld: How did you become interested in the connection between mitochondria and bipolar disorder? Were you surprised to find this integral relationship?
Dr. Adreazza: My interest developed from the observation that bipolar disorder is not only a disorder of mood regulation, but also a disorder associated with systemic metabolic and inflammatory abnormalities. Over many years, studies from our group and others identified oxidative stress, altered mitochondrial enzymes, and cell-free mitochondrial DNA in blood and brain samples from individuals with bipolar disorder. Those findings made mitochondria a compelling biological link between cellular metabolism, immune activation, and neuronal function. I was not surprised that mitochondria were involved, but I was struck by how clearly the organoid model connected these domains. In the same patient-derived system, Dana El Soufi El Sabbagh and the team could observe impaired mitochondrial energetics, increased mitochondrial stress signals, heightened NLRP3 inflammasome sensitivity, and altered neuronal firing. That integration is important because it moves us beyond isolated biomarkers and toward a mechanistic framework for understanding how cellular stress may influence brain circuit function.
MitoWorld: What is next for this research?
Dr. Adreazza: The immediate priority is to expand the cohort and incorporate clinical information that may explain biological heterogeneity, such as illness stage, predominant polarity, medication exposure, metabolic status, inflammatory burden, and treatment response. We also want to improve the organoid platform by adding greater cellular complexity, including microglia and vascular-like components, because immune and metabolic signalling in the brain depends on interactions among multiple cell types. Longitudinal organoid studies will allow us to follow mitochondrial function, inflammasome activity, and neuronal excitability over developmental time. Another important direction is therapeutic screening. Patient-derived organoids can help us test whether targeting the mitochondria-inflammasome axis restores cellular homeostasis and whether responses differ among individuals. Ultimately, our goal is to integrate organoid biology with blood-based biomarkers, such as cell-free mitochondrial DNA and metabolomic profiles, to move toward more precise, mechanism-based interventions for bipolar disorder.
MitoWorld: Anything else you would like the audience to know?
Dr. Adreazza: I would like to emphasize that this work was highly collaborative. Dana El Soufi El Sabbagh, the first author, led the experimental work across iPSC culture, cerebral organoid generation, mitochondrial assays, inflammatory assays, data analysis, interpretation, and manuscript preparation. The project also depended on an international partnership with our Australian colleagues at Deakin University, IMPACT and Barwon Health, whose expertise in clinical phenotyping, patient selection, and sample preparation made the patient-derived model possible. We are deeply grateful to the individuals living with bipolar disorder, as well as the healthy control participants, who contributed samples and trusted us to use them responsibly. Their participation allows us to study disease mechanisms in a human cellular context that would otherwise be inaccessible. I hope the audience sees this study not as a final answer, but as a platform for building more biologically precise and compassionate approaches to understanding and treating bipolar disorder.
Reference:
iPSC-derived cerebral organoids reveal mitochondrial, inflammatory and neuronal vulnerabilities in bipolar disorder. El Soufi El Sabbagh, D., Kolinski Machado, A., Pappis, L., Beroncal, E. L., Ji, D., Nader, G., Ravi Chander, P., Choi, J., Duong, A., Jeong, H., Panizzutti, B., Bortolasci, C. C., Szatmari, A., Carlen, P., Hahn, M., Attisano, L., Berk, M., Walder, K., & Andreazza, A. C. (2025). Translational Psychiatry, 15, Article 303. https://doi.org/10.1038/s41398-025-03529-7
Melanoma cells release abnormal mitochondria into the extracellular compartment. This novel mitochondrial quality-control mechanism points to possible biomarkers for the disease. The results of the study were recently published in a paper in Cancer Letters and led by Francisca Alcayaga-Miranda.
Melanoma cells experience significant levels of oxidative stress. While they depend on glycolysis, they still need mitochondria for other cell functions. Other studies had shown that damaged mitochondria are expelled from a stressed cell. However, it was not known if this process occurred with melanoma cells and how it was accomplished.
The research team sought to clarify this process. Using electron microscopy, they examined mitochondria released from normal and melanoma cells from mice. All cell lines released damaged mitochondria. The differences were found in the amounts of mitochondria released and the routes. The mitochondria were released through a non-vesicular route. Furthermore, the expelled mitochondria lacked cristae and had multiple other indications of loss. Complementary analyses showed that melanoma cells do not degrade mitochondria through canonical mitophagy in conditions of oxidative stress. Instead, melanoma cells upregulate mitochondrial release to the extracellular medium. With this data, the team concluded that the melanoma cells release mitochondria as an alternative mitochondrial quality control mechanism.
Interestingly, the mitochondria expelled from the melanoma cells were detected in the tumor microenvironment and plasma of the mice. The levels of those mitochondria correlated with the tumor burden. In agreement with these findings, more total extracellular mitochondria were also detected in the circulation of melanoma patients, supporting the translational relevance of this phenomenon.
The study revealed a novel mechanism for releasing dysfunctional mitochondria. It also points to new strategies for non-invasive biomarkers and therapies.
A Statement of Significance from Dr. Alcayaga-Miranda:
This study expands the conceptual framework of mitochondrial quality control in cancer by showing that melanoma cells can externalize structurally and functionally altered mitochondria into the tumor microenvironment and circulation. Rather than being confined to intracellular degradation pathways, mitochondrial dysfunction in melanoma may generate extracellular signals that reflect tumor-associated stress, mitochondrial quality-control imbalance, tumor burden, and systemic disease progression. These findings open two important horizons: first, the development of minimally invasive biomarkers based on circulating extracellular mitochondria, and second, the need to define whether tumor-derived mitochondrial material is only a consequence of mitochondrial stress or also an active mediator of immune modulation and metastatic niche formation. Thus, this work provides a foundation for future mechanistic and translational studies aimed at understanding extracellular mitochondria as both measurable indicators and potential functional players in melanoma progression.
A Conversation with Dr. Alcayaga-Miranda:
MitoWorld. This is rich study filled with experimental detail. Can you give us an idea of what you are considering to follow up on this research?
Dr. Alcayaga-Miranda: Our next step is to determine whether extracellular mitochondria released by melanoma cells are merely a consequence of mitochondrial stress or whether they actively contribute to tumor progression. We are particularly interested in understanding how this mitochondrial material interacts with the tumor microenvironment, especially immune cells, and whether circulating extracellular mitochondria can be further developed as minimally invasive indicators of tumor burden and disease progression.
MitoWorld. It is interesting that multiple mechanisms are available to expel mitochondria. Do you have any thoughts on why these exist?
Dr. Alcayaga-Miranda: Cells likely rely on more than one mechanism to eliminate or externalize mitochondria because mitochondrial quality control is highly context-dependent. Depending on the intensity of cellular stress and the capacity of intracellular degradation pathways, damaged mitochondria may either be degraded within the cell or exported through alternative routes. In melanoma, our findings suggest that extracellular mitochondrial release may represent an additional layer of mitochondrial quality control, particularly when mitochondrial stress is sustained or canonical degradation pathways are insufficient.
MitoWorld. You indicate that melanoma release mitochondria into the bloodstream. It is amazing that so many mitochondria are circulating. Do you have any estimates of that or of how long they circulate before being completely eliminated?
Dr. Alcayaga-Miranda: At this stage, we do not yet have precise estimates of how long extracellular mitochondria remain in circulation. This is an important open question. Their persistence is likely influenced by structural integrity, association with vesicular or non-vesicular compartments, recognition by phagocytic cells, and clearance by organs involved in filtering circulating particles. Future kinetic studies will be necessary to define their half-life, clearance routes, and whether these parameters change during tumor progression.
MitoWorld. There have been other reports that mitochondria are transferred from tumor cells to normal cells, such as immune cells. Did you see any evidence of this in your studies?
Dr. Alcayaga-Miranda: In this study, we focused primarily on demonstrating that melanoma cells release dysfunctional mitochondria into the tumor microenvironment and circulation. We did not directly evaluate mitochondrial transfer to immune cells as a central endpoint. However, the detection of tumor-derived mitochondrial material in the tumor microenvironment raises the possibility that these structures may interact with stromal or immune cells. This is one of the directions we are now actively exploring, particularly in relation to how tumor-derived mitochondria may influence antitumor immune function.
MitoWorld. Do you have any plans to pursue the development of biomarkers?
Dr. Alcayaga-Miranda: Yes. One of the translational horizons of this work is to determine whether circulating extracellular mitochondria can be developed as minimally invasive biomarkers. Before clinical implementation, several steps are required, including analytical standardization, rigorous control of pre-analytical variables during blood processing, validation in larger patient cohorts, and comparison with established clinical parameters. Our current data provide a strong rationale for this direction, but biomarker development will require systematic validation.
MitoWorld. We are always interested in what sparked your interest in mitochondria. Can you tell us?
Dr. Alcayaga-Miranda: My interest in mitochondria began with the idea that they are not only intracellular powerhouses, but also dynamic signaling organelles capable of shaping cell behavior and intercellular communication. In cancer, this is particularly fascinating because tumor cells continuously adapt their metabolism under stress. Understanding how mitochondria move beyond the cell may reveal new dimensions of tumor biology and open unexpected translational opportunities.
Reference
Georges-Calderón N, Fuentes C, Hidalgo Y, Grunenwald F, Corrales-Bermúdez J, Figueroa-Valdés AI, Ramirez-Pereira M, Arriagada G, Bustos FJ, Ahumada-Marchant C, Lopez M, Alcayaga-Miranda F (2026) Melanoma cells release dysfunctional mitochondria to the tumor microenvironment and circulation in association with tumor progression. Cancer Letters 647: 218457.
https://www.sciencedirect.com/science/article/pii/S030438352600220X?via%3Dihub
Dysfunctional mitochondria are associated with serious diseases (e.g., neurodegenerative disorders, heart failure), and transplantation of healthy mitochondria to diseased cells has been suggested as a possible therapeutic strategy. Recently, a research team, led by Botond Roska, developed a system for transplanting mitochondria to specific cell types. Their MitoCatch system is an exciting advance in harnessing mitochondria in therapies. The study was published recently in a paper in Nature.
The Roska team sought to identify protein binders that would facilitate the uptake of donor mitochondria by specific target cells. They engineered a series of such binders for their MitoCatch system. Using this system, they showed that the donor mitochondria were internalized into the cytosol and that they behaved as normal mitochondria exhibiting movement, fusion, and fission. In addition, the researchers showed that the mitochondria could be targeted to specific cell types, including retinal, cardiac, endothelial, and immune cells, and neurons. Most importantly, the diseased or damaged cells receiving the donor mitochondria had improved survival and function.
In a relatively short time, mitochondrial transfer has moved from fantasy to reality. The development of MitoCatch now provides a method for targeting specific disease cell types. This exciting advancement brings mitochondrial transfer closer to a therapeutic strategy for serious disease conditions.
A Statement of Significance from Dr. Roska:
Many diseases that involve malfunctioning mitochondria currently have no effective treatment. Transplanting healthy mitochondria into diseased cells has emerged as a promising therapeutic approach, but until now, there has been no reliable way to deliver them to the right cell types in the body. We developed a system called ‘MitoCatch’ that uses protein-based targeting tools to guide healthy mitochondria directly to affected cells. In laboratory experiments with human cells and in live mice, MitoCatch-delivered mitochondria improved the survival of damaged nerve cells. MitoCatch thus offers a new strategy for treating diseases linked to mitochondrial dysfunction by delivering healthy mitochondria precisely where they are needed.
A Conversation with Dr. Roska:
MitoWorld. Your work offers lots of intriguing possibilities. Can you give us an idea of where you are going next to follow up on this paper?
Dr. Roska: We are particularly interested in understanding how long donor mitochondrial DNA can persist in recipient human cells, as this information is important for therapy development. We are also optimizing our bispecific protein binders for specific human applications.
MitoWorld. Your work also has obvious clinical possibilities. Do you plan to exploit those as well?
Dr. Roska: Yes. Our goal is to develop MitoCatch into a therapy. We are in discussions with leading physicians across different medical fields to identify which mitochondrial diseases would be the best fit for the first MitoCatch-based treatments. LHON is among the first candidates.
MitoWorld. We have been following the emergence of mitochondrial transfer for some time. Are you as amazed as we are about how quickly it has been accepted as a fact and as a potential therapy?
Dr. Roska: This is indeed a fascinating field that is moving ahead at lightning speed. There are still sceptics who question the usefulness of mitochondrial transfer as a therapy, but this is healthy in science. The best way to respond to skepticism is to demonstrate the value of mitochondrial transfer in the clinic.
MitoWorld. In the Discussion, you mention that your system, like mitochondria free in the blood, did not elicit an immune response upon transfusions. That’s an interesting observation for your work and evolution. Can you speculate on that?
Dr. Roska: The key question is what these free mitochondria in the blood are doing — whether they are functional or waste products. This is not yet known, and the answer will have important implications for therapy.
MitoWorld. Clearly, mitochondria are the focus of MitoWorld, and we also enjoy hearing what brought researchers to the study of these amazing organelles. Can you tell us how you became interested in mitochondria?
Dr. Roska: About eight years ago I was thinking about the complexities of different therapeutic modalities. Gene therapy introduces one or at most a few genes into the body and so carries very low genetic complexity. Cell therapy, on the other hand, brings all of a cell’s genes into the body and, therefore, operates at extremely high complexity. I wondered whether therapies with an intermediate level of genetic complexity were possible. This led me to think about organelles and mitochondria in particular. At the time, very few papers had been published on mitochondrial transfer, but this has since changed dramatically, and I am very happy to be part of such an exciting and fast-growing field.
Reference
Ayupov T, Moreno-Juan V, Curtoni S, Fratzl A, et al. (2026) Cell-type-targeted mitochondrial transplantation rescues cell degeneration. Nature 15: