MitoWorld: The text notes that you enjoy thinking about “crazy” ideas. What is the “craziest” idea that intrigues you now?
One idea I’ve had for years is to replace the electron transport chain, complex I, III, and IV, for only two proteins. One would be an NADH dehydrogenase from yeast (for example NDi1), and the other would be an alternative oxidase (AOX). These can move electrons from NADH to oxygen, bypassing the traditional complex I/III/IV pathway. But here’s the crazy part: they don’t pump protons. That’s where proteorhodopsin comes in. It’s a light-driven proton pump. So, the idea is to express NDi1 and AOX in mitochondria to maintain redox balance and electron flux, and then express proteorhodopsin to regenerate the proton gradient using light. That proton gradient could then be used by ATP synthase to produce ATP.
But it gets even crazier. What if the AOX or NDi1 steps themselves could be engineered to emit light as a byproduct of electron transport? Then proteorhodopsin could be activated by that endogenous light, creating a feedback loop: electrons generate light, light drives proton pumping, protons drive ATP synthesis. In theory, with only three proteins—NDi1, AOX, and proteorhodopsin—we could reconstruct a functional, energy-producing electron transport system in mammalian mitochondria.
It’s very ambitious—perhaps impossible—but it has fascinated me since I was a student. The goal isn’t just synthetic biology, but to explore whether we can dissect the respiratory chain’s functions: electron flux, proton pumping, and ATP synthesis. These functions are often tightly coupled, but in biology, it’s not always beneficial for them to be. If we could separate them, we might gain insight into how they contribute independently to mitochondrial and cellular physiology. Whether I’ll ever be able to do it before the end of my career, who knows?
MitoWorld: A controversial hypothesis is that mitochondria move from cell to cell and that these transfers might serve as the basis for therapies. Do you have any thoughts about that possibility?
We not only have thoughts, but we also have experiments. In cardiac tissue, for example, mitochondria are packaged into membrane-bound structures we call “exopheres” and released. These are then taken up by neighbouring macrophages, which degrade them in a tightly regulated process. It’s a form of quality control but not necessarily a functional mitochondrial donation.
We’ve also shown, with Francisco Sánchez-Madrid, that mitochondrial components, especially mtDNA, can be transferred via immune synapses. The recipient cell sees that mtDNA as a danger signal, triggering antiviral responses.
Now, some studies—particularly in cancer—suggest that mitochondria can be taken up by recipient cells and remain functional, contributing to cell survival. However, while labeled mitochondria seem to transfer between cells, there’s little definitive evidence that they remain functional in the recipient cells or integrate into their networks.
The effects observed may often be immune related rather than metabolic. For instance, injecting mitochondria into blood has been proposed as a therapy, but the doses used are minuscule compared to endogenous mitochondrial populations in cells. Any physiological effects are more likely immune-mediated than due to actual mitochondrial “colonization.”
So, I think mitochondrial transfer happens, yes, but mainly as a signaling or quality control process. The notion of mitochondria behaving like autonomous, transferrable symbionts is still speculative.
MitoWorld: Can you speculate on how cells might regulate the specialization of mitochondria?
Between cell types, it’s mostly transcriptional regulation: different cells express different mitochondrial proteins or isoforms. But even within a single cell, mitochondria can be very different. One possible explanation is temporal regulation. A cell might express different sets of mitochondrial proteins at different times (e.g., day vs. night), and since mitochondria are relatively long-lived, this might create functionally distinct subpopulations. Another possibility is spatial regulation. Mitochondria traveling to different parts of the cell might encounter localized signals (e.g., specific mRNAs, post-translational modifiers, or regulators of protein import) that tune their function to local demands. In principle, if mitochondrial transfer between cells were robust, one could imagine specialized mitochondria being produced in one cell type and shared with another. But again, that’s still speculative.
MitoWorld: The role of mitochondria in energy production ensures that they are critical to cell and organismal health. Do you have any thoughts on how this might translate directly to health and aging?
Here I take a somewhat contrarian view. I don’t believe mitochondria drive aging. Aging is ultimately a consequence of entropy, a physical rather than strictly biological phenomenon. Biological systems resist entropy via repair and homeostasis, but over time, these processes lose efficiency.
That said, mitochondrial dysfunction is certainly part of the picture. As the cell accumulates damage (e.g., lysosomal inefficiency, metabolic imbalance, chronic inflammation), mitochondrial quality suffers. But so does everything else. For example, if oxygenation drops in the blood, the heart compensates by beating harder. Chronic compensation leads to hypertrophy and, eventually, pathology. The failure isn’t just in one organ or cell type; it’s in the integrated function of the whole.
So, while supporting mitochondrial function can help maintain cellular health, it won’t “cure” aging. In other words, mitochondria reflect the overall fitness of the cell. They are important, yes, but not supreme. Many age-related interventions that “target mitochondria” probably act through broader systemic effects: diet, exercise, metabolic control.
MitoWorld: Reversal of ATP synthase is counterintuitive. As you note, it might suggest a role in mitochondrial quality control. Can you elaborate on this hypothesis?
This might seem controversial at first: consuming ATP to pump protons. But it makes sense when you consider that the mitochondrial membrane potential must be tightly regulated. If it drops too low, apoptosis can be triggered. If it gets too high, ROS levels rise. So, reverse ATP synthase activity is a safety valve. It helps maintain an optimal membrane potential, even if doing so costs energy. In this light, ATP synthase becomes not just a producer of energy but a key regulator of mitochondrial homeostasis.
MitoWorld: FGR and OM1A are encoded by the nuclear DNA and imported into the mitochondria. That suggests a complex process with multiple potential therapeutic targets. Do you have thoughts about the most effective mechanism to inhibit it if it is not simply the enzymatic activity?
The challenge is that these enzymes have multiple substrates. Inhibiting their entire activity entirely can have off-target effects. A better strategy is to selectively block their interaction with specific targets, while leaving other interactions intact. Now that we know their structures, we can start designing molecules that interfere with specific protein-protein interactions to disrupt pathological effects while preserving beneficial ones. This is a more nuanced and promising strategy for targeting multifunctional mitochondrial regulators.
MitoWorld: One of the key questions in mitochondrial biology is how the mitochondria and the nucleus work together to keep things running smoothly—or not—when something goes wrong. Do you think your population studies might help us understand that relationship better?
This is a very important question. One of the biggest challenges in mitochondrial biology is that most mitochondrial protein complexes are assembled from proteins encoded by two different genomes: the mitochondrial genome and the nuclear genome. This creates a need for very tight coordination between the two, despite the fact that they evolve at different rates and under different selective pressures.
From a population genetics perspective, we can use large datasets to ask: (I) Which positions in these proteins are highly conserved (i.e., intolerant to change)? (II) Which positions vary more across individuals or species (i.e., more permissive to variation)? Some variants in mtDNA are never observed in the population, suggesting they are incompatible with nuclear-encoded partners.
We recently created a database scoring every amino acid in mitochondrial and nuclear-encoded ETC proteins for its permissivity—how often it varies across species and individuals. This helps us identify evolutionarily constrained sites where mitonuclear compatibility is critical.
We also see that mitochondrial and nuclear subunits in physical contact tend to co-evolve, whereas regions not in contact evolve more independently. This helps us map critical interaction interfaces and might uncover regulatory hotspots we don’t yet understand.
So yes—population studies can teach us a lot about mitonuclear compatibility, evolutionary constraints, and potentially, disease susceptibility.
Preface:
If we consider that mitochondria are the power plants of the cell, it may come as no surprise that they house a complex array of molecular machines, fine-tuned to churn out copious amounts of energy. What is remarkable, however, is that the blueprints for this machinery are rolled up in two distinct genomes—one nuclear, the other mitochondrial. This dual-genome system presents both challenges and opportunities to the cell in its never-ending quest to produce energy and adapt to an ever-changing world.
Each day, we synthesize roughly our own body weight in adenosine triphosphate (ATP) molecules, the universal energy currency that powers nearly every biological function1. Mitochondria—abundant in virtually all human cells—are the primary source of this ATP, synthesizing it from the oxygen we breathe and the nutrients we consume. The molecular machines that perform this astonishing work, every moment of every day, are situated in the inner mitochondrial membrane (IMM) and are known as the respiratory complexes (RCs). Together, complexes I through IV create an electrochemical gradient of protons across the IMM; these protons subsequently pass through complex V, driving its rotary mechanism and catalyzing ATP synthesis.
For these RCs to function efficiently, nearly 100 protein subunits must assemble in the IMM—a feat made more complex by the need to coordinate expression across two separate genomes: the diploid nuclear genome and the numerous circular copies of mitochondrial (mt)DNA distributed throughout the dynamic mitochondrial network. Significant genetic mismatch between these genomes can result in mitonuclear incompatibility, disrupting OxPhos assembly and ATP production.
Although the molecular mechanism of OxPhos is coming into focus in increasingly granular detail, an ambitious new study—published in Cell Genomics, from the lab of José Antonio Enríquez—traces the fundamental role of evolution in shaping the RC subunits at both the population and individual levels2. Over the course of more than 6 years, the authors conducted detailed analyses of each of the OxPhos subunits, integrating comparative genomics, protein structural modeling, and rigorous statistical analysis to produce a comprehensive map of both the diversity and the evolutionary constraints operating within this critical energy-producing system.
Notably, examination of more than 2,500 genotypes in the 1000 Genomes Project revealed an unexpected plasticity in the extent to which individuals could assemble different versions of the OxPhos machinery, based on the inherent variability stemming from diploidy and heterozygosity (i.e., different versions of the same gene coming from maternal and paternal chromosomes). For example, over 90% of people analyzed in this study could assemble at least two configurations of complex I. In the cases of complexes IV and V, no individual could assemble only a single version of the molecular machines. Thus, contrary to prior assumptions, the OxPhos machinery is not a rigid structure but a dynamic ensemble, that assembles in multiple configurations, depending on an individual’s genetic makeup. Moreover, a systematic analysis of individual amino acid residues—encoded by mtDNA, X, or autosomal chromosomes—demonstrated that the mitochondrial genome, due to its elevated mutation rate, represents a key source of variation and adaptability in human populations.
To further probe the evolutionary dynamics of the OxPhos proteins, the authors developed a novel methodology, called ConScore, for evaluating the extent to which specific amino acid residues are conserved across evolution. How compatible OxPhos protein subunits may be with one another depends substantially on how well they fit together in the larger 3D macromolecular complexes. Therefore, interface residues (IFRs) represent key determinants of mitonuclear compatibility. While interface residues (IFRs) in nuclear-encoded subunits—particularly those encoded on autosomes—are highly conserved, those in mtDNA-encoded subunits are surprisingly variable. This increased plasticity likely reflects an evolutionary mechanism that facilitates compatibility between divergent nuclear and mitochondrial genomes, especially at heterologous binding sites.
Despite this flexibility observed in heterologous IFRs encoded by mtDNA, 65–75% of all OxPhos residues exhibit no variability. Moreover, for many OxPhos genes, one of the two alleles is preferentially expressed, a phenomenon known as allelic imbalance. This early developmental bias constrains which subunits are effectively produced, thereby limiting the potential variability at the protein level—even when multiple variants are present in the genome.
Overall, this study illuminates the evolutionary forces that shape the essential OxPhos machinery. It reveals how cells balance strict functional requirements with surprising structural plasticity—maintaining energy production while allowing adaptability through mechanisms like mtDNA variation, allelic imbalance, and isoform diversity. These findings deepen our understanding of mitochondrial biology and offer insights relevant to disease, aging, and speciation.
MitoWorld: Oxidative phosphorylation requires the coordinated assembly and activity of numerous protein subunits from the nuclear and mitochondrial genomes. What was the inspiration for your study, and what key gaps in knowledge did you aim to address at the outset?
Mito-nuclear incompatibilities are widely recognized not only as drivers of speciation but also as key contributors to mitochondrial diseases in humans. The goal of our study was to better understand the evolutionary trajectory of oxidative phosphorylation (OxPhos) from vertebrates to modern human populations at the finest possible resolution—down to individual amino acid residues. We focused on two main objectives. First, we aimed to identify evolutionary patterns among respiratory complexes or subunits, distinguishing them based on their coding genome or mode of inheritance (mtDNA-encoded, nuclear autosomal-encoded, or X-chromosome-linked). Second, we sought to refine the current understanding of functional constraint in human OxPhos proteins at the residue level, by comparing conservation patterns across nested phylogenetic scales: vertebrates, mammals, and primates. All analyses and interpretations were conducted with a strong emphasis on molecular 3D structures, which serve as the central framework of this work.
MitoWorld: From an evolutionary perspective, what key differences did you identify between the mitochondrial and nuclear genomes?
The behavior of these two genomes shows distinct variation in relation to the respiratory complexes, most notably in complexes I (CI) and IV (CIV). Our findings suggest that mitochondrial DNA (mtDNA) functions not only as an evolutionary driver, facilitating speciation, but also exhibits a continuous dynamic role. This supports the hypothesis that the capacity for change (defined by the mutational rate of mtDNA) is a conserved trait. At the population level, this capacity for change enables mtDNA to undergo selective sweeps that help to balance the heterozygosity in nuclear-encoded OxPhos subunits. The result is the emergence and maintenance of viable mitonuclear combinations that highlight a cooperative, co-evolutionary process between the two genomes.
MitoWorld: Your study integrated genomic analyses with structural data. How did bringing together information from these different disciplines enhance your overall understanding of the OxPhos system?
Genetics or genomics and structural biology, although developed and studied as independent branches of biology, are deeply interconnected. Genetic changes often gain biological and evolutionary significance when they manifest as phenotypic traits, particularly through alterations in proteins, whose function is closely tied to their 3D structure. Moreover, certain evolutionary trends can only be observed by examining their impact on protein structures, such as the differential evolutionary patterns in binding sites.
MitoWorld: You used extensive datasets like the 1000 Genomes Project and gnomAD v3. Were there any limitations or biases in these datasets that might affect how we interpret the variability and constraints you observed?
Certainly, these databases, while representing a significant effort to cover human variability, are far from a comprehensive picture of the human genetic diversity. Therefore, we complemented human variation data with comparative analyses across other phylogenetic groups, anchoring our interpretations in evolutionary conservation and maintaining a focus on human protein structures. This cross-species perspective allows us to broaden our understanding of the functional significance of specific residues by examining their tolerance to change.
MitoWorld: Throughout your analysis, what results did you find most unexpected, and how did they shift your view of the respiratory complexes?
One of our most surprising findings was the prominent role of heterozygosity as a critical source of individual genetic variability, supported by analysis from the 1,000 Genomes Project. In a biological system, such as OxPhos, which is governed by the interplay and coevolution of two separate genomes, this observation raised the fundamental question about how such variability is managed at the molecular level. This led us to investigate allelic imbalance as a possible mechanism. To delve deeper, we focused on a pronounced example (hybrids between subspecies). Our findings revealed that allelic imbalance serves not only as an evolutionary means to mitigate heterozygosity but also as an indicator of additional regulatory complexity. It directly impacts the precise coordination required for the expression and assembly of multi-component systems; mismatches in this process may predispose to disease. Another striking result was how strongly selective pressures shape the 3D landscape of functional constraints within OxPhos complexes. This 3D map reflects the intricate evolutionary pressures at play on protein structure and function at the residue level.
MitoWorld: To evaluate the extent to which individual amino acid residues of the respiratory complexes are conserved, you developed a methodology called ConScore. Can you explain how this works and why it can shed light on the impact of mutations in different regions of a protein?
ConScore measures how conserved a specific position in a protein is, helping us to understand how likely it is to tolerate mutations. It combines information from variations in humans and other species (using sequence alignments) to show which changes at that position are allowed by evolution.
MitoWorld: How do you think that ConScore could be leveraged to characterize the genetic underpinnings of different pathologies associated with OxPhos dysregulation, such as mitochondrial diseases, cancer, or neurodegeneration?
Benchmarking results suggest that the ConScore can be directly applied to variant prioritization. However, to realize its full clinical potential, we envision two complementary directions for future development. First, we aim to evaluate its applicability beyond OxPhos components, extending its use to proteins that interact with OxPhos pathways. Second, we propose incorporating ConScore as a feature within machine-learning models to develop a more refined tool for assessing the pathogenicity of mutations.
MitoWorld: Mitochondrial transplantation or transfer involves the incorporation of mitochondria through different strategies, such as injection, vesicular transport, or intercellular bridges. Your study highlights the importance of mitonuclear incompatibility. How can we potentially optimize the coordinated expression and function of the hundred or so OxPhos subunits in the context of potential therapies?
Our previous work already found that this may be a relevant issue from a clinical point of view (PMID: 35236094; PMID: 32832682; PMID: 31588014; PMID: 27383793). Here we developed and refined in silico models of the OxPhos respiratory complexes that can be used to investigate ConScore-guided sequence variations in nuclear and mtDNA-encoded OxPhos components to anticipate compatibility issues, supporting further research in this area.
MitoWorld: Your work suggests that the high mutation rate of mtDNA is not just a vulnerability but may be an adaptive feature. Do you think that mtDNA mutability itself has been selected for during evolution?
The answer is yes. The symbiosis that led to the origin of eukaryotic cells incorporated mtDNA from the very beginning. Therefore, the mutation rate of each chromosome, including the mtDNA, has been optimized for evolutive success. This idea was also suggested by Wallace in 2010. In our study, we observed that, compared to nuclear-encoded subunits, the variability in mtDNA-encoded subunits is higher between species (with some exceptions, depending on the respiratory complex) and within human populations. Moreover, interface residues in mtDNA-encoded subunits show greater variability than other regions of the same proteins, suggesting a relaxation of selective constraints that is maintained even among humans.
These patterns support the idea that mtDNA mutability should not be understood as a vulnerability, but rather an evolved feature that contributes to functional flexibility and adaptive potential, especially in the context of mito-nuclear coevolution. The increased mutation rate in mtDNA could allow more rapid exploration of sequence space, enabling compensatory adaptations in response to changes in nuclear-encoded partners or environmental pressures. While more evidence is needed to confirm whether mtDNA mutability itself has been directly selected for, our results are consistent with the hypothesis that this feature plays an adaptive role in fine-tuning oxidative phosphorylation and maintaining mito-nuclear compatibility.
MitoWorld: What are some big outstanding questions relating to how evolution molds the OxPhos machinery?
Well, a challenge to address is investigating the functional differences in the OxPhos system among phylogenetic groups and their adaptive significance across various ecosystems. This exploration should occur at the residue, protein, respiratory complex, and supercomplex level.
References:
1. Lane, Nick (2018) Power, Sex, Suicide: Mitochondria and the Meaning of Life. Oxford University Press, Oxford, UK.
2. Cabrera-Alarcón JL, Rosa-Moreno M, Sánchez-García L, Agustín PH, Jiménez-Gómez MC, Martínez F, Sánchez-Cabo F, Enríquez JA (2025) Structural diversity and evolutionary constraints of oxidative phosphorylation. Cell Genom. 100945. doi: 10.1016/j.xgen.2025.100945. Epub ahead of print. PMID: 40614727.
We are happy to announce that Dr. Dane M. Wolf, recently an EMBO Long-Term Fellow at the University of Cambridge, is starting his own mitochondrial microscopy consultancy and will serve as MitoWorld’s Director of Microscopy.
Wolf is a mitochondrial biologist specializing in advanced imaging technologies. He completed his PhD at Boston University and University of California, Los Angeles, where he used live-cell super-resolution microscopy to study the structure-function relationship of mitochondrial cristae. As an EMBO Long-Term Fellow at the University of Cambridge, he investigated mitochondrial (mt)DNA dynamics using cutting-edge imaging approaches.
Wolf founded MitoGraphica, a scientific consultancy focused on mitochondrial image analysis and research, to support both academia and industry. He is deeply passionate about mitochondria and is committed to advancing and communicating our understanding of their vital roles in human health and longevity.
“In my lab, Dane became an imaging virtuoso,” said Dr. Orian Shirihai, Wolf’s PhD mentor, “not just because of his technical skill, but because of his creativity and attention to detail. What he’s built with MitoGraphica is a natural extension of his scientific work: a consultancy grounded in rigor, reliability, and precision. He brings not only innovation and vision, but also the discipline to deliver timely, well-documented, statistically sound solutions to complex image analysis challenges—something the field truly needs.”
MitoWorld: You assembled a nice slide deck (download PPTX) tour of some of the imagery you produced while at UCLA. Can you say a little bit about what we see in that deck?
Wolf: It’s an overview of the imaging that I performed at UCLA. The lab focused not only on the role of mitochondria in single cells, but also on how they regulate metabolism across the body. I spent a lot of time imaging a pancreatic β cell line (INS-1) and primary hepatocytes—which carry out the bulk of the liver’s metabolic activity. The deck also includes images of antibody-producing B cells undergoing mitosis in response to a stimulatory signal, along with super-resolution imaging of cristae, lipid droplets, lysosomes, and mtDNA in a variety of cell types.
The main takeaway from this set of images is that virtually all eukaryotic cells are densely populated with mitochondria. They inhabit the cell almost like individuals in a village—exhibiting complex behaviors, being born and dying, in a manner of speaking—and recent work suggests they take on specialized roles within the broader cellular environment. Remarkably, mitochondria can even travel between cells via membranous bridges or vesicles, coming to the aid of stressed neighbors.
MitoWorld: Which came first, your interest in mitochondria or imaging? How did the two evolve together for your work at UCLA and then Cambridge?
Wolf: I’ve been interested in the biology of aging for as long as I can remember. Since mitochondria are central to cellular homeostasis—and their dysfunction is closely linked to the systemic decline associated with aging—my interest in mitochondria came first. That said, it wasn’t until I began my PhD and saw live mitochondria under a confocal microscope that this interest grew from an abstract, academic curiosity into something visceral and compelling. There’s something truly captivating about looking through a microscope and watching thousands of mitochondria wiggle and dart around a field of cells, sometimes undergoing fusion and fission. In those moments, mitochondria seem to exhibit their own kind of behavior. That sense of wonder made me want to follow them more closely, and I became increasingly focused on developing approaches that would allow me to visualize them in greater spatiotemporal detail. The more clearly you can see them— really scrutinize their movements—the more their inner life begins to emerge, in surprising and often beautiful ways.
MitoWorld: During your PhD at UCLA in the Shirihai Lab, what were you trying to accomplish with imaging that you or the lab thought was beneficial, and how did this work add to the field of mitochondrial microscopy?
Wolf: In Orian’s lab, there has always been a strong emphasis on mitochondrial dynamics—how mitochondria move, divide, and fuse. As a PhD student, I was fortunate to have a great deal of freedom to explore, and at UCLA, we had access to cutting-edge super-resolution imaging technologies. One of these systems, Airyscan, allowed us to visualize mitochondria beyond the optical diffraction limit, opening up new possibilities for studying their complex internal structures in live cells.
By optimizing this technology, we developed methods to resolve the inner mitochondrial membrane in living cells. Using membrane-potential-sensitive dyes, we discovered that cristae—the characteristic folds of the inner membrane—were more polarized than other regions, and that individual cristae within the same mitochondrion could display distinct membrane-potential signatures. This supported a new model of the proton motive force, in which the electrical potential that drives ATP synthesis is compartmentalized at individual cristae. In this model, each crista functions like a miniature battery within the larger mitochondrion—much like how a Tesla battery pack is made up of many smaller battery cells (see Wolf et al., 2019).
This level of compartmentalization is thought to enhance energy efficiency. Just as importantly, it provides a form of bioenergetic buffering—if one crista becomes damaged or dysfunctional, it doesn’t compromise the entire organelle. Crista-level autonomy hadn’t been fully appreciated before, and this work added a new layer of understanding to mitochondrial resilience and function.
MitoWorld: Can you briefly describe the range of imaging techniques that you used to investigate mitochondria and how they aid in fundamental research?
Wolf: The imaging techniques that we used are primarily Airyscan and structured illumination microscopy (SIM), two different types of extended or super-resolution microscope. Airyscan employs a 32-channel GaAsP detector array in place of a traditional single-point detector, allowing it to capture more spatial information from the Airy disk of emitted light. Each detector element collects light from a slightly different position, and the combined data are computationally reconstructed to enhance both resolution and signal-to-noise ratio. This approach enables imaging beyond the diffraction limit, down to approximately 120 nm in the x-y plane. Airyscan is also highly sensitive, allowing us to image mitochondria using relatively low laser power. This reduced phototoxicity was critical for measuring membrane potential, as mitochondria are prone to depolarization when exposed to laser-induced stress.
SIM, by contrast, works by projecting striped patterns of light onto a sample from multiple angles and phases. These patterns create moiré interference with fine cellular structures, effectively shifting high-resolution information into a detectable range. By capturing a series of these patterned images and applying computational reconstruction, SIM achieves resolution beyond the optical diffraction limit—down to approximately 120 nm or roughly twice the resolution of conventional confocal microscopy.
Without super-resolution techniques, we wouldn’t be able to resolve the fine details of mitochondrial architecture without resorting to electron microscopy, which requires fixation or freezing, ruling out real-time measurements of structure and function. To truly understand something, you have to see how it moves. Super-resolution microscopy allows us to visualize the dynamics of mitochondria’s innermost structures, shedding light on core aspects of their function.
MitoWorld: What other works of yours might be forthcoming?
Wolf: In many ways, my work in Cambridge built upon the skill set I developed at UCLA. I applied a combination of super-resolution and 4D imaging to investigate the dynamics of the mitochondrial genome. This work is still unpublished, so I can’t go into detail just yet, but I’m looking forward to sharing it with the community, as I believe it offers new insights into fundamental aspects of mitochondrial function.
MitoWorld: Where do you think the field will go over the next 5 years? What do you hope to perfect and investigate over this time?
Wolf: Naturally, it is difficult to predict where the field will go. But if I had to guess, I’d say mitochondrial biology will become increasingly integrated with other disciplines. There’s a growing recognition that mitochondria are fundamental to a wide range of cellular functions, and mitochondrial dysfunction has emerged as a hallmark of an expanding list of diseases.
We’ve known since the mid-20th century that mitochondria are the cell’s powerhouses. A conceptual leap at the end of that century was the realization that they also play a central role in determining whether a cell lives or dies. The 21st century has brought about a renaissance in mitochondrial biology, with new discoveries revealing their involvement in diverse physiological contexts—from maintaining stem cell identity to driving specific cancer behaviors through shifts in metabolic activity.
I’m particularly interested in the role of mitochondria in the aging process. Finding new ways to preserve or rescue mitochondrial function, especially under stress, will likely be essential in efforts to combat age-related diseases such as neurodegeneration. And of course, I am always working to stay at the forefront of imaging technology, as visualizing mitochondrial behavior in ever-increasing detail continues to unlock new insights.
MitoWorld: How do you hope to shape your business, and what services can you bring to labs to improve or design their microscopy for cutting-edge research?
Wolf: After studying mitochondria for over a decade, I’ve come to appreciate that mitochondrial shape is a powerful indicator of function. This isn’t surprising—structure and function are fundamentally intertwined. Understanding how and why mitochondria change shape can reveal important clues about their physiological state, which in turn affects cellular and even organismal homeostasis.
That said, accurately measuring mitochondrial morphology is far from trivial. It requires not only high-quality imaging, but also the expertise to use specialized analysis platforms capable of segmenting and quantifying complex mitochondrial networks. Interpreting these changes—and uncovering the mechanisms behind them—can be especially challenging for researchers who aren’t specialists in mitochondrial dynamics or function.
Given the growing interest in mitochondria across both industry and academia, I founded www.MitoGraphica.com to make this expertise more accessible. The goal is to support researchers who want to image mitochondria but need guidance, as well as those who already have images but require expert help with analysis and interpretation. Ultimately, progress in both basic biology and therapeutic development depends on rigorous experimental design and accurate data. I want MitoGraphica to be a reliable resource—ensuring that anyone studying mitochondrial function has access to the tools, insights, and support needed to do it well.
If our website is MitoWorld, the Mechanisms of Mitochondrial DNA Mutation and Repair conference was the introductory gathering of what could be called “mtDNA World.”
The organizers, Patrick Chinnery (Cambridge), Agnel Sfeir (Sloan Kettering) and Michal Minczuk (Cambridge), emphasized that this conference focused solely on mtDNA is a first of its kind.
“This brand-new conference will focus on understanding how mitochondrial DNA mutations occur in the germ line and somatic tissues with age and how they contribute to common diseases, including neurodegeneration and cancer. The conference will also cover mitochondrial DNA’s molecular and cellular consequences and new approaches to repair and remove mutations.” [conference website]
The global mitochondria conference circuit generally is focused on mitochondria themselves (often in primary mitochondrial disease) in all their complexity with a smaller percentage of presentations on mtDNA itself. In Nashville, June 1–5, about 75 individuals representing labs globally, went deep into a range of heteroplasmy dynamics over lifetimes and in various disease and dysfunction cases. There was a sense of the importance of mtDNA and its relationship with the nuclear DNA as a primary and secondary driver of disease and dysfunction and also as part of the fundamental aging process.
“The result was an interactive meeting that highlighted the current multi-functional nature of mtDNA (beyond its known role in ATP production) and the cutting-edge new techniques and approaches now available to understand how mtDNA genes are expressed, how mtDNA mutations contribute to human physiology and pathology, and how we can now edit mtDNA or otherwise modulate this maternally inherited genome to improve human health,” said Gerry Shadel (Salk Institute).
The conference was very participatory and, since it was held in Nashville, ended with an evening of line dancing.
In the words of some of the organizers and attendees:
Agnel Sfeir, Organizer, Sloan Kettering
The meeting exceeded our expectations in every way. The quality of the science, the level of engagement, and the sense of community were truly exceptional. One of our goals was to create a space that fostered open discussion across disciplines and career stages, and I think we succeeded, which was evident by the engagement of trainees, the quality of their presentations, and the insightful questions they asked.
Dmitry Temiakov, Thomas Jefferson University
The conference’s exclusive focus on mitochondrial DNA was both timely and highly valuable for the scientific community. By concentrating on mtDNA, the meeting brought together researchers across diverse disciplines—from genetics and structural biology to clinical medicine—who might otherwise not engage in direct dialogue. This focused format fostered in-depth discussions on unresolved questions, including the mechanisms underlying mitochondrial diseases, maternal inheritance, and the role of mtDNA in inflammation and aging.
Maria Falkenberg, The Falkenberg Lab, University of Gothenburg
The meeting was a unique and refreshing experience, being the first to focus only on mtDNA. It gave space for interesting discussions that went all the way from basic science to possible new treatments. The talks covered many parts of mtDNA biology, from how it is maintained to how it can be targeted in disease. It was great to see the community come together around a topic that is often included in bigger meetings, but not usually the main focus.
Gerald Shadel, Salk Institute
Our genome comprises nuclear and mitochondrial DNA, both of which are essential for life and contribute to human diseases and aging. The biology and genetics of mtDNA is complex due to it being present in multiple (often thousands) copies/cell and its sequence dynamically changing in our bodies as we age. While there are many meetings on nucleic acids (DNA and RNA), genetics and even mitochondria, rarely is mtDNA a central theme. This FASEB meeting was therefore unique by focusing a lens on mtDNA and effectively bringing together many of the senior researchers who have long influenced our understanding of mtDNA with exciting new investigators in the field.
Carlos T. Moraes, University of Miami
It was right time for a meeting focused on my favorite genome (mtDNA). There have been so many advances in our understanding and manipulation of mtDNA in the last few years, and it was exhilarating to hear and discuss them with experts and colleagues. My recent area of work is mtDNA editing, and new techniques have opened a whole area of investigations and therapeutic development. As always, new knowledge raises many questions, so this meeting was a great forum to generate new ideas and how to overcome barriers, such as the off-target edits of mtDNA base editing.
Amutha Boominathan, MitoSENS
The conference provided a comprehensive overview of recent advances in mitochondrial DNA research, with a strong focus on its role in cellular function and pathology. A key highlight was the application of advanced sequencing technologies to resolve mitochondrial heteroplasmy at the single-cell level and to establish genotype-phenotype correlations. It brought together students and junior and established researchers, with particular emphasis on emerging topics, such as mitochondrial regulation of immune responses, novel metabolic functions, and targeted approaches to silence/modulate the mitochondrial genome. The meeting was highly interactive and engaging. Looking forward to the follow-up!
Olvia Conway, Duke University
This meeting was extremely valuable to me as a trainee because of the networking and learning opportunities available. My mtDNA project is a new area for the lab, so this meeting was a way to meet others focused on this topic, receive feedback on some of my early work, and determine in which direction the field is heading. I am grateful for the opportunity to talk to other scientists during the conference sessions, and I am planning on implementing many of the suggestions I received. This was my first meeting as a graduate student, and I had a great experience.
MitoWorld’s life sciences reporter, Danny Levine of the Levine Media Group, conducted an in-depth video interview or MitoCast with Dr. Thompson as part of MitoWorld’s Spotlight series.
Watch the video on YouTube here.
In March, Gary Howard, MitoWorld’s editorial lead, wrote a MitoWorld post about Craig Thompson’s Lab at Memorial Sloan Kettering (MSKCC) and their detailed analysis of a new type of mitochondria devoted to building cell structures, not just producing ATP. Howard summarized Thompson’s and his collaborators work in Nature, Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
Howard wrote, “The laboratory of Craig Thompson reports that, under stress conditions, mitochondria assume different roles. Dr. Thompson is the former president and CEO of Memorial Sloan Kettering Cancer Center (2010-2022) and currently holds the Douglas A. Warner III Chair in the Cancer Biology and Genetics Program.
“Dr. Thompson’s research team began their search with a careful rethinking of mitochondrial functions. While mitochondria have many key functions, they are best known for producing the energy that we all need from the food that we eat.” [Sloan Kettering Press Release]
Ana Andreazza, PhD, professor of pharmacology and toxicology at the University of Toronto’s Temerty Faculty of Medicine, leads the Mitochondrial Innovation Initiative, Mito2i, a research hub at University and affiliated institutions and hospitals.
The new project, MitoRevolution: Mitochondrial Transplantation Transforming Regenerative Medicine — from research to patient care to global impact, is part of the university’s
Institutional Strategic Initiative portfolio, is supported by a $23.8-million grant from the Canadian federal government’s New Frontiers in Research Fund Transformation Stream and brings together an interdisciplinary team that is committed to transforming regenerative medicine through mitochondrial transplantation.
Mitochondrial transplantation is defined as the process of introducing new mitochondria into cells, tissues or organs, and mitochondrial transfer is the natural movement of mitochondria between cells or into bodily fluids.
These processes are both controversial, and mitochondrial transplantation as a therapy is viewed with a considerable skepticism. Nevertheless, there is a growing interest in research into transplantation for emergency, resuscitation and regenerative purposes. Some cases have yielded positive results. However, those results cannot be attributed to an increase in mitochondrial capacity and function or to actions by the immune system or other reactions.
The infusion of federal funding in Canada to explore the wide-ranging question posed by mitochondrial transplantation marks the first nationally funded initiative of its kind.
Discussion with Dr. Andreazza
MitoWorld: There seems to be a real divergence in the thinking in the scientific community of whether transplantation is real in terms of transplanted mitochondria taking up their full functions once transplanted. How do you and the team answer those questions?
Andreazza: Indeed, this divergence is a major reason our team has come together under the NFRF-Transformation grant. Rather than assuming one mechanism over another, our approach is to systematically evaluate how transplanted mitochondria interact with host cells, whether by integrating functionally, or by initiating signaling pathways that support recovery or regeneration. Using innovative tools such as live imaging, mitochondrial tagging, and 3D tissue models, we aim to directly observe and measure mitochondrial behavior post-transplantation.
MitoWorld: On the other hand, there is the fear that the patient communities, especially those who have mitochondrial genetic diseases or are parents of children who do, will have their hopes falsely raised in the short term. How do you and your team counsel the mitochondrial patient community at this point?
Andreazza: We are deeply aware of the responsibility we have to the patient community. Transparency is central to our approach. While mitochondrial transplantation holds promise, we are careful not to frame it as a near-term therapeutic option for genetic mitochondrial diseases. Instead, we emphasize that this is an early-stage scientific endeavor with an initial potential for ex-vivo organ regeneration. We engage with patient groups regularly. In fact, the MitoCanada Foundation was part of the design of the project from the beginning, and it is now forming patient and communities committee that will oversee the project development. Most importantly, listening to concerns and co-developing knowledge translation strategies are central to ensure expectations remain grounded in the realities of where the science currently stands.
MitoWorld: Where do you and the cross-disciplinary and cross-institutional team hope to focus first, and what solutions or findings do you anticipate?
Andreazza: Our first focus is to establish the mechanism that underlies mitochondrial transplantation. Using 3D tissue and animal models, we hope to determine how mitochondria survive transfer, how long they persist in recipient cells, what cells uptake mitochondria, and what outcomes they influence. We’re particularly interested in ex-vivo organ regeneration for improvement of organ transplant. From this foundational science, we hope to develop tools that can guide future clinical applications, including standardized protocols and safety metrics.
MitoWorld: It would seem that Canada is the first national government to make an investment in mitochondria transplantation. What do you think motivated decision from a policy, scientific, and treatment perspective?
Andreazza: Canada’s investment reflects the country’s forward-looking research framework that embraces high-risk, high-reward strategies. It aims to elucidate the roles of mitochondria in health and in nearly every major disease with an opportunity to transform our understanding, and hopefully treatment strategies. In my view, these opportunities made this a compelling story for support under the NFRF’s Transformation Stream. Additionally, the interdisciplinary and community-driven nature of the project aligns well with Canada’s emphasis on collaboration and innovation.
In a recent paper published in Nature Communications, a research team led by Nick Jones at Imperial College London explored the relationship between mutations in mitochondrial DNA and aging. More specifically, they examined “cryptic mutations” that are somatic mtDNA mutations unique to single cells in the sample.
The team accessed publicly available sequencing of the nuclear and mtDNAs of 140,000 individual cells from four mammalian species and seven tissues. Both DNA types show increased numbers of mutations with aging. As assumed, the increase in nuclear DNA mutations was linear. However the mtDNA showed a nonlinearity. In fact, the number of mutant genomes in a cell reached high levels around the time when the effects of aging are seen in humans. Although these results are surprising, they are also consistent with previous studies that show that mice with more rapid rates of mtDNA mutation age more rapidly.
They also noted that the rise of mtDNA mutations correlates with key aging manifestations, such as protein misfolding, endoplasmic reticulum stress, and markers of neurodegeneration.
Conversation with Dr. Alistair Green and Prof. Nick Jones
MitoWorld: These are intriguing results. Others have suggested that infusions of healthy mitochondria into cells would have therapeutic benefits. Might they also slow the aging process?
Jones: This could be a fertile direction to pursue, though there is not much evidence that large amounts of mtDNA are transferred into cells.
MitoWorld: Mitochondria are associated with many key cellular functions, but they have genes for little more than energy production. Can you speculate on the mechanism that links these mutations to aging? Could it be as simple as the loss of ability to produce energy, or is there more?
Green: Loss of energy production is definitely the leading order concern, but there are other mechanisms that could be at work. Mito-nuclear mismatch has been known to impair function, and we see a stress response in cells carrying cryptic mutations. If mutant mtDNA is released into the cytoplasm this could also be causing this stress response.
MitoWorld: Your results seem to correlate with caloric restriction as a mechanism to slow aging. Interestingly, that would seem to lower available energy levels. Can you comment on that seeming contradiction?
Green – While severe caloric restriction can lower energy levels, the opposite is true for mild restriction. Mitochondria can become more efficient and crucially for our model, cells can switch on mitochondrial biogenesis, increasing the number of mitochondria in cells. This increase in copy number is what our model predicts would slow the ageing we observe.
MitoWorld: Could there be some “cryptic” signaling between the mtDNA and nuclear DNA to account for this correlation?
Jones: Trying to establish just what is causing the correlation is definitely the focus of future work. Some signaling between nuclear DNA and mitochondrial DNA is definitely one avenue of investigation.
MitoWorld: Did you find any particular mtDNA mutation that seemed to stand out or were they more or less equally distributed?
Green: They are fairly evenly distributed across the genome, excepting the known mutational hotspot by the origin of replication. The lack of selection we see would support that cells have a hard time identifying mutations in any particular region that they might be less tolerant to.
MitoWorld: What do you see as the next steps in this research?
Jones: We would like to corroborate these effects in more proliferative cell types.
MitoWorld: How did a mathematician become interested in mitochondria?
Jones: There are multiple copies of mtDNA in a cell and the fluctuations in that number, and the number of mutations they contain, is quantifiable and presents tricky mathematical challenges. Simultaneously the products of this single quantifiable entity have wide-reaching cell physiological effects: this is thus a setting where bringing together stochastic modelling, inference, informatics and experimental design can yield transformative insights.
MitoWorld: Another recent paper reports on mtDNA mutations and aging (Wang, Z., Li, Z., Liu, H. et al. Mitochondrial clonal mosaicism encodes a biphasic molecular clock of aging. Nat Aging (2025). https://doi.org/10.1038/s43587-025-00890-6). Do you have any thoughts on that paper?
Jones: This recent interesting paper is based on using bulk-RNA seq — our paper first appeared on bioRxiv two years ago and is focused on single cells and thus gives a direct insight on the process at hand.
Reference
Green AP, Klimm F, Marshall AS, Leetmaa R, Aryaman J, Gomez-Duran A, Chinnery PF, Jones NS (2025) Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species. Nat Commun 16: 2250. https://doi.org/10.1038/s41467-025-57286-8
In a paper in Nature Communications, a multi-institution research team, led by Phillip West at The Jackson Laboratory, describes hyperactivity of the innate immune system in models of polymerase gamma (PolG)-related mitochondrial disease (VanPortfliet et al., 2025). This work advances understanding of how mitochondrial diseases impact the immune system and identifies potential therapeutic targets to limit immunopathology and other infection-associated complications.
Mitochondrial diseases (MtDs) are the most common inborn errors of metabolism. Although patients with MtD do not appear to have more viral and bacterial infections than others, emerging research suggests infections can result in more severe outcomes, including sepsis and death. The relationship of MtDs and inflammation has therefore become a topic of considerable interest in the research community. Mitochondrial dysfunction can activate the innate immune system, which responds with inflammation that, when unregulated, further damages mitochondrial activity.
In their paper, West’s team delved further into this problem. More specifically, they examined two mouse models that carry deleterious mutations in the PolG gene (PolgD257A and PolgR292C). They found that these mutations, which impact mitochondrial DNA (mtDNA) stability, result in chronic activation of the type I interferon (IFN-I) pathway in immune cells and tissues. Furthermore, they uncovered that IFN-I hyperactivates another immune sensor called caspase-11, which senses bacterial cell wall components and promotes inflammatory cell death in macrophages. This form of cell death, called pyroptosis, is critical for control of bacterial infections, but must be tightly regulated because it promotes the release of cytokines and other factors that lead to a strong inflammatory response. When innate immune cells from the PolG mutant mice were infected with bacteria, they underwent pyroptosis much more readily and caused a dramatic increase in inflammatory responses. This overactive innate immune response was also seen when PolG mutant mice were infected with bacteria.
Although these PolG mutant mice do not recapitulate all aspects of PolG-related MtDs, chronic activation of the innate immune system, increased inflammatory responses, and other symptoms are seen in MtDs in humans. Thus, this experimental system is an excellent model for studying innate immunity in MtDs.
A Conversation with Dr. West
MitoWorld: What caused you to become interested in mitochondria and MtDs?
West: I have been studying the interplay between mitochondria and the innate immune system since my PhD training at Yale. I somewhat stumbled into mitochondrial biology during my thesis research, but have been fascinated by these organelles ever since. As a postdoctoral fellow with Gerry Shadel, I found that mtDNA release is a potent trigger of interferon and inflammatory responses. As all of our early work was in cells, I wanted to translate our findings into animal models when I opened my own lab. We hypothesized that because MtDs have dysfunctional mitochondria and often exhibit mtDNA instability, there may be an unappreciated role for immune dysfunction in these diseases. We are addressing this hypothesis in mouse models of MtD, including the PolG mutants used in this paper, but are also striving to translate our results into understanding immune dysfunction in human MtDs.
MitoWorld: Under normal circumstances, the immune system is carefully regulated. Too little control is thought to allow cancers to grow. Too much results in autoimmune diseases. MtDs are yet another source of immune dysregulation. Do you have ideas about how to follow up your work in humans?
West: We are working collaboratively with Dr. Peter McGuire’s group at the NIH/NHGRI, who are also studying in immune dysregulation in MtDs. We were fortunate to be included on Peter’s recent study (Warren et al., 2023) that revealed interferon and inflammatory gene signatures in the white blood cells of patients with diverse MtDs. There was significant overlap in the immune signatures seen in patient cells and two of our mitochondria mutant mice, so we do feel our animal studies correlate with human data. Our goal now is to identify immunotherapeutics that may be used to restore proper immune function and limit infection-related complications in individuals with MtDs.
MitoWorld: It’s interesting that MtD patients are more susceptible to infections and have an enhanced innate immune response. During the Covid pandemic, any vaccination was thought to activate the innate immune system and protect (to a degree) against coronavirus infection. Is the MtD case, just another example of the immune system gone awry?
West: This is an interesting question. I think it is important to highlight that the immune phenotypes in MtDs will probably be diverse and not manifest in exactly the same ways. For example, those with Barth syndrome often have neutropenia, or to few neutrophils, and are susceptible to bacterial infections. In addition, Dr. Anu Suomalainen-Wartiovaara’s group recently reported reduced antiviral responses in patient samples and mice carrying the PolG MIRAS allele, suggesting that there may be dramatic differences in immune phenotypes even within PolG-related MtDs (Kang et al., 2024). Other MtDs may cause hyperactive innate immunity, whereas some may lead to problems with adaptive immunity (i.e., antibodies and T cells). We are early in these studies, and MtDs are rare diseases, making it often difficult to obtain large patient cohorts for study. However, we can rapidly advance the field by generating new, more relevant animal models of MtD and coupling these findings with data from human studies.
MitoWorld: MtDs manifest at different ages. Do you have any ideas about what might activate the immune system in an MtD?
West: We hypothesize that mitochondrial dysfunction in MtDs basally alters the tone of immune cells. This is likely due to small amounts of cytokines and other stimulatory factors being released constitutively. For example, we showed that the aberrant release of mtDNA and other nucleic acids triggers the innate immune system in the absence of infection. Metabolic alterations in MtDs can also profoundly impact immune cell development and function. In the context of infection, innate immune cells, such as macrophages, may mount an overactive response, and this can feed forward to damage mitochondria and trigger subsequent rounds of mtDNA release or elevate metabolic crisis.
MitoWorld: So many of the former mitochondrial genes are now part of the host genome. Could mutations in those genes cause similar problems in mitochondria?
West: Most of my lab’s work has focused on examining innate immune responses in mouse models where nuclear-encoded mitochondrial genes are missing or mutated. However, others are examining immune responses in patients and animal models with particular disease-relevant mtDNA mutations. For example, Dr. Martin Picard has shown that cells from patients carrying a single, large-scale mtDNA deletion have blunted inflammatory cytokine responses (Karen et al., 2022). In contrast, a mouse model carrying a heteroplasmic mtDNA mutation (m.5019A>G) mirroring that seen in humans exhibit a hyperinflammatory immune status characterized by elevated interferon (Marques et al., 2025). Therefore, mutations in nuclear and mtDNA encoded mitochondrial genes can impact the immune system.
MitoWorld: How do you plan to extend this research?
West: My lab and colleagues at JAX are working to expand the toolkit of mouse models for MtDs, and we are excited to send our new models into labs around the globe. I am quite hopeful that MitoWorld, the UMDF, the PolG Foundation, and other advocacy groups will better unite researchers examining immunological issues in animal models and patients with MtDs.
* Two hours after infection, macrophages were stained with antibodies and dyes to mark the cell membrane (white), mitochondria (green), the nucleus (blue), and Pseudomonas bacteria (magenta). Cells were then imaged on a confocal microscope. The macrophage at the bottom right is undergoing pyroptosis, an inflammatory cell death pathway resulting in nuclear condensation, membrane permeabilization, loss of mitochondria, and release of cytokines.
References
Kang Y, Hepojoki J, Sartori Maldonado R et al. (2024) Ancestral allele of DNA polymerase gamma modifies antiviral tolerance. Nature 628: 844–853.
Karan KR, Trumpff C, Cross M, Engelstad KM, Marsland AL, McGuire PJ, Hirano M, Picard M (2022) Leukocyte cytokine responses in adult patients with mitochondrial DNA defects. J Mol Med (Berl) 100: 963–971.
https://pmc.ncbi.nlm.nih.gov/articles/PMC9885136/ (PubMed Central)
https://link.springer.com/article/10.1007/s00109-022-02206-2 (behind paywall)
Marques E, Burr SP, Casey AM, Stopforth RJ, Yu CS, Turner K, Wolf DM, Dilucca M, Tyrrell VJ, Kramer R, Kanse YM. An inherited mtDNA mutation remodels inflammatory cytokine responses in macrophages and in vivo. bioRxiv 2025 Jan 5:2025-01.
https://www.biorxiv.org/content/10.1101/2025.01.05.631298v1
VanPortfliet JJ, Lei Y, Ramanathan M, Guerra Martinez C, Wong J, Stodola TJ, Hoffmann BR, Pflug K, Sitcheran R, Kneeland SC, Murray SA, McGuire PJ, Cannon CL, West AP (2025) Caspase-11 drives macrophage hyperinflammation in models of Polg-related mitochondrial disease. Nat Commun 16: 4640.
https://doi.org/10.1038/s41467-025-59907-8
Warren EB, Gordon-Lipkin EM, Cheung F et al. (2023) Inflammatory and interferon gene expression signatures in patients with mitochondrial disease. J Transl Med 21: 331. https://doi.org/10.1186/s12967-023-04180-w
The UMDF Mitochondrial Medicine for Scientists and Clinicians Mitochondrial Medicine 2025 conference provides an international stage for leaders in mitochondrial medicine and offers programs to inspire the next generation of researchers. Attendees will learn about the latest developments in the field of mitochondrial medicine, including industry advancements, potential treatments, therapies and cutting-edge research. The event also gives the scientific communities the unique experience of engaging with affected patients to better understand symptoms and work faster towards a cure. This year’s conference is being held in St. Louis, Missouri on June 18-21, 2025. https://www.umdfconference.org/
Jonathan Brestoff, MD, PhD, MPH, leads the Brestoff Lab and is Associate Professor of Pathology & Immunology, Director of the Initiative for Immunometabolism, and Medical Director in the BJH Clinical Flow Cytometry Lab at WashU Medicine in St. Louis.
We asked Jon to explain a bit about this his work and what is being organized from the scientific and medical community at UMDF 2025.
MitoWorld: Jon, how did you become involved with the UMDF Clinical & Scientific Program?
Brestoff: My lab has been working on trying to develop mitochondria transplantation as a new therapy for primary mitochondrial diseases, and this work has gotten me engaged with the UMDF. With the meeting being in St. Louis, they sought a local presence on the organizing committee. I’m very honored to help with this meeting and think it will be very exciting!
MitoWorld: What can researchers and clinicians expect from this year’s program?
Brestoff: This conference includes an amazing lineup of speakers on diverse scientific topics on mitochondrial biology and clinical issues in mitochondrial medicine. Main scientific sessions include Inflammation and Metabolic Diseases, Mitochondria on the Move, Mechanisms of Clearing Damaged Mitochondria, and Multi-omics. Clinical sessions include the NAMDAC Registry Session, Mitochondrial Medicine Society Platform, and Clinical Trial Updates. On Saturday, there are 2 parallel Master Classes, one on emerging clinical topics chaired by Dr. Michio Hirano and one on scientific career development chaired by me.
MitoWorld: Is there any particular theme or emphasis this year?
Brestoff: The main themes are around emerging scientific discoveries about mitochondria and clinical updates. One of the most exciting aspects of this meeting is that patients, families, clinicians, and scientists all come together for one conference. This creates a unique experience that, in my experience, has been incredibly motivating and inspiring.
MitoWorld: With your lab at Washington University in St. Louis, will you be discussing or your lab members presenting on your lab’s work?
Brestoff: Yes! While I am not speaking to yield time to other investigators, a couple exceptionally talented scientists from my group are presenting their work on mitochondria transfer and transplantation.
MitoWorld: What are your hopes in your work for the next year and what issues are on the forefront that may materialize over the next year?
Brestoff: There are so many new and exciting discoveries about mitochondria — how they work, what they do, and how we can leverage their biology to develop new therapeutics. There is tremendous untapped potential in this field for many diseases, not just primary mitochondrial diseases but also others like obesity, heart disease, and even aging. I hope we can find ways to team up with each other, industry partners, and investors to make some of these new therapeutics a reality for patients who need them. For my own lab, we’re currently working to make mitochondria transplantation a future possibility for patients with primary mitochondrial diseases. I hope we can get there.
In a review paper in Endocrine Reviews, Rachel Varughese and Shamima Rahman of University College London describe the effects of primary mitochondrial disease on the endocrine system and how these diseases can be diagnosed and treated.
Mitochondria provide the energy for the production and export of many cellular products. Mutations that affect mitochondrial function can disrupt the production of key molecules, including endocrine hormones. The result might be diabetes, growth hormone deficiency, adrenal insufficiency, hypogonadism, and parathyroid dysfunction. In fact, the authors suggest that the possibility of underlying mitochondrial dysfunction should be considered in all hormonal diseases. Thus, understanding how the mitochondria are involved in those diseases is critical.
Primary mitochondrial disorders (PMDs) are genetic disorders that affect the structure or function of the mitochondria. Because mitochondria are so intimately involved with multiple cellular functions, mitochondrial mutations can manifest in many disorders. The mutation can occur in either the nuclear or mitochondrial genome.
Varughese and Rahman provide an extensive review of how mitochondria can be damaged and of the diseases that can result. They conclude by noting that clinicians should be suspicious of a PMD for any patient who has an atypical presentation or seemingly unrelated comorbidities. The treatment of PMDs can be complex and quite different than the “normal” treatment for a particular endocrine manifestation.
A conversation with Rahman and Varughese
MitoWorld: Since there is no cure for PMDs right now, are clinicians left with treating the symptoms?
Rahman: Yes, symptomatic management is the mainstay of managing PMDs at present. This means being vigilant and monitoring for known complications of the disease and acting promptly with symptomatic measures when these complications arise.
MitoWorld: You seem to be suggesting that clinicians should be aware of multiple, possible unusual combinations of symptoms that might indicate a PMD. Are there key diseases other than diabetes that should raise suspicion?
Rahman. Table 6 in our paper gives several examples of combinations of symptoms that should arouse suspicion of an underlying PMD. For example, the combination of adrenal insufficiency or growth hormone deficiency with progressive external ophthalmoplegia, pigmentary retinopathy and heart block should alert the clinician to the possibility of Kearns-Sayre syndrome, while the combination of premature ovarian insufficiency and sensorineural hearing loss is suspicious of Perrault syndrome.
MitoWorld: What are the most promising treatments that you are aware of?
Rahman: Unfortunately, there are no disease-modifying therapies that are licensed for PMDs. Many treatments are in development at the preclinical stages, including pharmacological and genetic approaches. Currently, genetic approaches seem more promising as strategies to provide personalized tailored curative treatments, but are not yet available for PMDs, with the exception of Leber Hereditary Optic Neuropathy.
MitoWorld: What interested you in mitochondrial in the first place?
Rahman: I first began caring for patients with mitochondrial diseases as a junior doctor (paediatric trainee) in the early 1990s. Deeply moved by the challenges faced by affected patients and their families, I have devoted my career to improving the diagnosis and management of these conditions.
Varughese: I am a paediatric endocrinologist. As a paediatrician, I was drawn to endocrinology by the opportunity to make lasting impacts on children’s growth and development through targeted, evidence-based care. My interest in mitochondrial disease emerged from seeing its intricate interplay with multiple organ systems, including endocrine function. Writing this article was a way to bridge both interests, aiming to improve both early recognition of endocrine issues in affected children and the identification of underlying mitochondrial disease in patients with atypical constellations of symptoms.
Reference
Varughese R, Rahman S (2025) Endocrine dysfunction in primary mitochondrial diseases. Endocrine Reviews 46: 376–396.