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