“There is a lot we can learn from putting together the mitochondria and cancer research fields, from a better understanding of basic biological processes to identifying metabolic vulnerabilities with clinical potential. I am particularly looking forward to seeing how the Mitochondria-Cancer Atlas Working Group will provide a higher resolution into mitochondrial function across cancer types and how it can be leveraged therapeutically.” Salvatore Fabbiano, PhD, Editor-in-Chief, Cell Metabolism

Cancer cells lead a harsh existence. To support their growth, they need large amounts of energy, but their environment involves hypoxia, metabolic competition, and nutrient scarcity. Interestingly, they manipulate that environment and particularly their mitochondria to mitigate those challenges.

Cancer presents a unique opportunity to understand how tumors manipulate mitochondria and to ask what those lessons mean both for the cancer community and mitochondrial biology. A commentary in Cell Metabolism by Thomas MacVicar, Laura Greaves, Payam Gammage, and Steven Tait of Cancer Research UK Scotland Institute, Kelsey Fisher-Wellman of Wake Forest University and MitoWorld’s Gordon Freedman expands on this insightful observation. The intersection of these two research fields has informed studies of metabolic reprogramming, mitochondrial genetics, and regulation of cell death.

The metabolic reprogramming of mitochondria is critical to cancer cells. For example, the accumulation of oncometabolites due to mutations drive cancers in distinct cell types. One of the more intriguing aspects of mitochondria is their ability to migrate from cell to cell to enhance tumor metabolism or to weaken immune cell defenses. As more is learned about changes in mitochondrial metabolism, the challenge becomes of how to translate these advances into possible new biomarkers and therapeutic strategies for the treatment of various cancers.

Mitochondria have their own small genome, and mutations in mitochondrial DNA (mtDNA) are widespread across tumor types but non-random. While the role of these mutations in cancer is not clear, mutation burden, heteroplasmy, copy number, and other factors may be involved. Normal age-related mutations seem to accumulate in tumors, and some others may be subject to selective pressures during tumor evolution. These features of mtDNA may have potential as biomarkers and therapeutic targets, and in turn, advances in cancer biology will elucidate principles of mitochondrial genetics.

Although mitochondria are best known for producing cellular energy, they also have a significant role in programmed cell death. In apoptosis, the mitochondrial outer membrane becomes permeable and release proteins that activate caspases. Tumors can circumvent this cascade of activities. Yet, this very weakness suggests a possible therapy by inhibiting caspases and encouraging anti-tumor immunity.

In the last few years, scientists and physicians have come to realize that mitochondria do so much more than simply transform cellular energy. They have fundamental roles in a wide variety of human diseases, such as cancer. However, the activities of cancer cells provide a means to study mitochondria and, in turn, elucidate the biology of cancer. This strategy might be particularly helpful in “threading the needle” to kill cancer cells while leaving normal cells untouched. The metabolic reprogramming, mtDNA mutations, or openings in programmed cell death offer new possibilities for treatments. One hopeful development by the authors and others has been the establishment of the Mitochondria-Cancer Atlas Working Group. They hope to use modern molecular methods to define quantitative measurements of mitochondrial physiology and apply those findings to cancer biology and treatments. Although cancer is the initial focus, those same processes will eventually be applied to the many other diseases associated with mitochondria.

“Mitochondria are intimately involved in so many aspects of our health,” said Gordon Freedman. “Our goal here is to leverage our knowledge of cancer and mitochondria to improve human health.”

A Conversation with the Authors.

MitoWorld: The Cell Press Symposium on “Multifaceted Mitochondria” will emphasize the close relationship between cancers and mitochondria. What are you looking forward to from that meeting?

MacVicar: The roundtable session dedicated to mitochondria in cancer will be a nice opportunity to discuss new ideas for characterizing mitochondrial signatures in tumors and identifying disease-specific metabolic vulnerabilities.

Greaves: I am particularly looking forward to the round-table discussion. It will be exciting to hear different perspectives from researchers working in cancer, mitochondrial disease, and basic mitochondrial research, and to explore where these fields overlap.

Fisher-Wellman: The conference will bring together experts in mitochondrial biology across multiple disciplines. This kind of interdisciplinary environment is often the best catalyst for new ideas and impactful collaborations.

MitoWorld: Your commentary describes three general areas of intersection between mitochondria and cancers. Is there one area that you think will yield patient benefit sooner than the others?

MacVicar: Metabolic reprogramming, mitochondrial genetics and cell death signaling are interconnected. Unveiling the interactions between these mechanisms will improve our chances of targeting mitochondria effectively in future cancer treatments.

Fisher-Wellman: Because all therapies must achieve a therapeutic window, I am bullish on leveraging the intrinsic biology of tumor cells to drive cancer-type–specific targeting. The success of CLPP activators is a strong example. Once specificity was achieved (CLPP is highly expressed in the indicated cancers relative to most all other tissues of the body), durable responses can follow.

Greaves: I think mitochondrial signaling and its role in cancer therapy resistance may be the fastest route to patient benefit. While targeting cancer metabolism is an attractive approach, I think we need to be cautious, given the potential for toxicity in healthy tissues. Understanding how mitochondrial function influences treatment response in specific cancer contexts may offer more selective ways to improve existing therapies and ultimately benefit patients.

MitoWorld: What has surprised you the most in your studies of cancer and mitochondria?

MacVicar: Coming from a background of studying mitochondria in cultured cell lines, I continue to be amazed by the metabolic crosstalk between cancer cells, immune cells and stromal cells within primary and metastatic tumor microenvironments.

Fisher-Wellman: The remarkable specialization that exists within and across cancers. They are certainly not all organized the same, and this creates a massive opportunity.

Greaves: What has struck me most is the extent of tissue specificity in mitochondrial function across cancers. While not entirely surprising given my background in ageing and mitochondrial disease, it has important implications for therapeutic development.

MitoWorld: Although mitochondrial exchanges between cells was controversial just a few years ago, it now seems to be real. Can you elaborate on how that feature might be leveraged in cancer biology?

Fisher-Wellman: Understanding how these transfer events reshape cancer cell biology and the surrounding immune microenvironment is an exciting area of exploration.

MitoWorld: Can you describe the work of the Mitochondria-Cancer Atlas Working Group and what you hope it will achieve?

Fisher-Wellman: Early efforts to target mitochondria in cancer were heavily skewed toward core energy transduction pathways that are ubiquitous across tissues. While this approach has not translated into clear clinical benefit, it has been informative. The key lesson is that mitochondria themselves are not drug targets per se; rather, the tissue- and context-specific biology encoded within them is actionable. The goal of the Atlas is to systematically define this specialized biology across cancer types, with the aim of enabling truly cancer-specific mitochondrial targeting strategies.

Greaves: I hope that by mapping mitochondrial biology across different cancers, we can gain a better understanding of tissue-specific mitochondrial dependencies and uncover new opportunities for therapy.

Freedman: MitoWorld became interested in cancer and mitochondria to help put definition around the mitochondria transfer question that is debated in the mitochondrial research community. It seemed that cancer provided an incredible long-term laboratory for what can be done to and with mitochondria. Once we examined this, it seemed an atlas of mitochondrial variation by cancer and tumor state would be useful, and we met up with Fisher-Wellman to organize a working group.

MitoWorld: What is your sense of how other researchers and clinicians are picking up on the association of mitochondria with cancer and other diseases?

Freedman: MitoWorld posted a MitoBlog about the mitochondria transfer session, Mitochondrial Transfer Networks in Cancer Progression, at this year’s American Association of Cancer Research. This was one of the first mitochondria sessions at a major cancer conference, and there was standing room only.

Fisher-Wellman: The idea that organelle biology is central to many aspects of cancer cell function is becoming hard to ignore. That said, it is still underappreciated just how different mitochondria are in their intrinsic biology. Mapping this specialization is critical for scaling mitochondrial-targeted therapies that can meaningfully translate to the clinic.

This will be great to learn more about at the MitoWorld roundtable session!

Reference

MacVicar T, Greaves LC, Gammage PA, Tait SWG, Fisher-Wellman KH, Freedman G (2026) Cancer as a window into mitochondrial biology. Cell Metabolism. In press.