Cancer Originates in Defective Mitochondria
- Thomas P Seager, PhD
- Jul 20
- 11 min read
Updated: Jul 25
Use cold plunge to target tumor metabolism
Summary
The somatic mutation theory (SMT) of cancer, which states that it originates in mutations that occur in the nucleic DNA, is not supported by the evidence and has made little progress in cancer treatment outcomes despite billions of dollars of research investment during the last five decades.
In fact, cancer originates in defects of the mitochondria that alter cell metabolism and result in failure to signal cell death via apoptosis.
Therapies that target the mitochondria, such as ketones and the ketogenic diet, improve cancer treatment outcomes.
Cold plunge therapy, in combination with nutritional and circadian support, may help prevent tumors and reverse cancer.
"The evidence is massive to support that cancer is a metabolic disorder." - Prof. Thomas Seyfried, Boston College, on 'Diary of CEO'
Cancer originates in defects of mitochondria
Although all major cancer research centers in the United States start from the supposition that cancer is a genetic disease that originates in defects of DNA in the nucleus, scientific evidence suggests otherwise. For example, Prof. Thomas Seyfried of Boston College explains that cancer originates in defects of the mitochondria, not the nucleus. Two lines of evidence support his assertion:
There is no instance in which cancer cells proliferate (reproduce) when the mitochondria they contain function properly. However, there are some instances in which cancer cells do have healthy nucleic DNA (Seyfried et al. 2025). This suggests that tumorigenic damage to the DNA is downstream of damaged mitochondria .
Transplantation of a healthy mitochondria into tumor cells with damaged nucleic DNA shrinks tumor volumes (e.g., melanoma in mice by Yu et al. 2021 and Fu et al. 2019, human breast cancer by Chang et al. 2019) and transplantation of a tumorigenic nucleus into cells with healthy mitochondria results in a normal, non-tumor cell (Seyfried 2015).
There are two characteristic features of cancer that are a direct consequences of dysfunctional mitochondria. The first relates to energy production within the cancer cell, and the second relates to a failure of cell death.
The metabolism of cancer
The energetic requirements of cancer are different from normal cells. In normal cells, efficiency and flexibility are of paramount importance to ensure that cell metabolism continues under conditions of resource scarcity. For example, in summer, fruits may be plentiful and consequently normal cells must adapt to a high carbohydrate metabolism driven by glucose and supported by bright sunshine. However, in winter fruits will be scarce and the body must adapt to either starvation or increased animal fats and fish in relative darkness. During those cold periods outside the growing season, or during famine, cell metabolism switches from carbohydrate-based to fat-based. An intermediary by-product of fat metabolism is ketones, which is why a very low carbohydrate diet is called ketogenic. This metabolic flexibility allows the body to function well under varied, or seasonal, conditions.
Ketones have several advantages as a metabolic substrate for normal cells. For example, they are extremely efficient, yielding more energy per unit than any other mitochondrial fuel (Veech 2004). Because they cross the blood-brain barrier, they provide a powerful metabolic basis for the brain. And ketones can enter the cell without the benefit of insulin, so that when a body is in ketosis, insulin levels remain low. In fact, ketones in the bloodstream protect against the adverse effects of hypoglycemia (i.e., low blood sugar) so that essential cognitive and other functions can be maintained even when dietary sources of carbohydrates are very scarce.
Nonetheless, cancer cells cannot metabolize ketones. Cancer metabolism does not rely on the mitochondria, as mitochondrial dysfunction is a defining characteristic of tumor metabolism. Instead, cancer cells bypass mitochondria to produce energy from a process called fermentation. The only fermentable substrates available to cancer are glucose and glutamine (an amino acid), because ketones will not ferment.
Fermentation serves the needs of cancer well, because although they lack flexibility and efficiency, what they get instead is speed. That is, it is possible to fuel rapid cell proliferation via fermentation, so long as glucose (and sometimes glutamine) are abundant. Therefore, cancer flourishes under hyperglycemia, when blood glucose levels are high (Zhang et al. 2022). That explains the strong association with cancer and insulin resistance (Bikman 2020).
How tumors grow forever
The second characteristic of cancer is the uncontrollable proliferation that eventually chokes off essential bodily functions and kills its host. In this way, cancer is parasitic. It steal resources from the body, redirects them into nothing but its own reproduction, accelerating its own eventual demise by destroying its host.
Normal cells do not do this. When normal cells cease to function well, they undergo death via apoptosis. With the exception of red blood cells (which do not contain mitochondria) apoptosis is signaled and controlled by the mitochondria. Thus, uncontrolled proliferation of tumor cells, including metastatic tumors (i.e., cancer) occurs only when the mitochondrial mechanisms for signaling apoptosis are disabled.
Targeting metabolism to treat cancer
To interrupt cancer metabolism, Seyfried recommends starving tumor cells of the glucose and glutamine on which they rely. That means finding ways to interrupt the flow of both glucose and glutamine from the bloodstream to tumor cells.
Ketones vs Cancer
Seyfried advocates for nutritional ketosis -- either by adopting a very low carbohydrate diet or taking ketone supplements, or both -- citing studies that show ketones inhibit tumor cell growth and improve cancer treatment outcomes (e.g., Duraj et al. 2024). For example, in mice with metastatic cancer, administering ketone supplements decreased tumor cell viability and prolonged life (Poff et al. 2014). More recently, a review of ketone bodies as an adjunctive therapy in human studies showed evidence that it improves outcomes of radiation and chemotherapy for brain, pancreas, breast, and other types of cancer (Liang et al. 2025).
The mechanisms are primarily metabolic. Because ketones are not fermentable, they cannot be metabolized by tumor cells, nor support tumor proliferation. Only cells with healthy mitochondria can process ketones, where they provide an ideal, efficient metabolic substrate. Moreover, having ketones available in the bloodstream allows the body to tolerate both lower blood glucose and lower insulin levels, energetically favoring normal cells and disadvantaging tumor cells. Secondarily, ketones likely interfere with modifications to the extracellular environment that enables tumor cells to evade attack by the immune system.
Can glutamine fermentation be blocked?
Glutamine is the most abundant amino acid in the bloodstream. It participates in hundreds of essential functions supporting muscle development, metabolism, and immune function. Depressing glutamine levels in the bloodstream to starve tumor cells could have serious adverse consequences on other essential body systems. Nonetheless, because glutamine fermentation is a viable metabolic pathway to support tumor proliferation, some cancers will not be treated by suppression of glucose alone. Seyfried and other recommended periodic pharmacological inhibition of glutamine to interrupt tumor cell metabolism.
Mitochondrial Therapies to Treat Cancer
As I wrote in Cold Therapy for Cancer, clinical research in animal models and humans beings has demonstrated the efficacy of non-shivering cold thermogenesis via activation of brown adipose tissue (BAT, or brown fat) for clearing glucose from the bloodstream to inhibit tumor growth (e.g., Seki et al. 2020). Moreover, in Ice Bath for Fast Keto I explained how cold plunge therapy is the fastest way to stimulate production of endogenous ketones. These mechanisms alone might help explain the seemingly miraculous treatment outcomes in two individuals who have successfully treated otherwise incurable cancers with ketosis and cold plunge.
Nonetheless, to date researchers like Seyfried have yet to assemble systematic experimental protocols for mitochondrial support that integrate disparate knowledge related to the metabolic theory of cancer. Because cancer originates in defects of mitochondria, it makes sense to me that a comprehensive suite of therapeutic interventions that support mitochondria could improve prognoses. For example, magnesium is essential to mitochondrial function and magnesium supplementation has been used successfully to support mitochondrial function. Therefore, it should be no surprise to learn that cancer patients with higher blood serum levels of magnesium experience better clinical outcomes than those with lower (Feng et al. 2024, Ashique et al. 2023). Other nutritional supplements that support mitochondria and may improve cancer treatment outcomes are L-Carnitine (Donisi et al. 2023), CoQ10 (Dabaghi et al. 2024), folate (and not folic acid, Pieroth et al. 2018), and PQQ (Min et al. 2014).
Other metabolic therapies also support cancer treatments. For example, when researchers tested red light against breast cancer cells in vitro, they discovered 660 nm irradiation promoted anti-proliferative activities via autophagy (Yang et al. 2021). Additionally, exercise creates anti-cancer properties in blood serum (Kurgan et al. 2017).
However, one of the best ways to rejuvenate mitochondria is cold exposure. For example, when mice were exposed to 72hr of cold air, the activation of their brown fat induced two processes relevant to mitochondrial quality: 1) mitophagy, which is the process by which defective mitochondria are destroyed, and 2) mitobiogenesis, which is the process by which new mitochondria are made. In combination, these two processes improve the overall health and function of mitochondria by eliminating the damaged and replacing them with new (Yau et al. 2021).
What remains unclear is the relationship between cold exposure and glutamine. To my knowledge, there has never been a study that investigated the effect of cold on glutamine levels in the blood -- despite the fact that glutamine participates as a metabolic precursor in gluconeogenesis, the process by which the body synthesizes new blood glucose from non-carbohydrate sources during periods of extreme exercise and/or carbohydrate-deficient diets (such as is ordinarily prescribed to induce ketosis). Experiments in baby chickens demonstrate that glutamine supplementation protects against adverse effects of cold exposure (Al-Khalaifah et al. 2025), suggesting a relationship between glutamine metabolism and activation of brown fat during non-shivering thermogenesis. Moreover, studies of human brown fat during cold activation have observed uptake of glutamine (Weir et al. 2018). However, subsequent studies have also suggested glutamine synthesis in brown fat during cold exposure (Park et al. 2023). Thus, the relationship between cold and glutamine metabolism remains mysterious.
Hallmarks of Cancer
Although cancer is often thought of as an invincible, inexorable destructive force, there are several unusual characteristic features that suggest cancer cells are more fragile than non-cancerous. There are several aberrant conditions that must be maintained to promote metastatic cancer growth (simplified from Hanahan 2022):
Modified cell metabolism relying exclusively on fermentation of glucose & glutamine without mitochondrial involvement,
Disabled mitochondrial signaling of apoptosis, to escape cell death,
Sustained angiogenesis (formation of new blood vessels) to support proliferation,
Establishment of a favorable extracellular tumor micro environment (e.g., inflammation, acidic pH) to avoid immune destruction,
Hijacked ordinary immune functions to enable metastasis.
All of these aberrant conditions must be maintained for cancer to flourish. By contrast, mutations in nucleic DNA that drive cancer are sometimes absent, suggesting that mitochondrial and immune system modifications precede nucleic DNA damage. That means nucleic gene therapies are unlikely to result in positive clinical outcomes when the five hallmarks listed above remain intact.
On the other hand, mitochondrial dysfunction directly results in metabolic modification and disabling of apoptosis, and contributes indirectly to all three others. Therefore, one of the best ways to prevent cancer is to avoid mitochondrial injury in the first place.
In graduate school, I was taught that carcinogenic environmental toxins caused cancer by inducing mutations in nucleic DNA. Now, I don't believe that's true. Instead, I think carcinogenic exposures likely act through the mitochondria. That is, these toxins cause mitochondrial damage first, and as a consequence of that damage, genetic mutations take place later. In this way, genetic mutations do not "drive" cancer -- they are merely passengers.
Mitochondrial therapies are cancer therapies. That means that caring for your light environment (e.g., maintaining a healthy circadian rhythm), avoiding seed oils, incorporating intermittent fasting or nutritional ketosis into your diet, and a regular practice of cold plunge therapy may be the best approach to both prevent and cure most cancers.
References
Al-Khalaifah H, Tolba SA, Al-Nasser A, Gouda A. Effects of Glutamine Supplementation and Early Cold Conditioning on Cold Stress Adaptability in Broilers. Animals. 2025 May 11;15(10):1386.
Ashique S, Kumar S, Hussain A, Mishra N, Garg A, Gowda BJ, Farid A, Gupta G, Dua K, Taghizadeh-Hesary F. A narrative review on the role of magnesium in immune regulation, inflammation, infectious diseases, and cancer. Journal of Health, Population and Nutrition. 2023 Jul 27;42(1):74.
Bikman B. Why We Get Sick: The Hidden Epidemic at the Root of Most Chronic Disease--and how to Fight it. BenBella Books; 2020 Jul 21.
Chang JC, Chang HS, Wu YC, Cheng WL, Lin TT, Chang HJ, Kuo SJ, Chen ST, Liu CS. Mitochondrial transplantation regulates antitumour activity, chemoresistance and mitochondrial dynamics in breast cancer. Journal of Experimental & Clinical Cancer Research. 2019 Jan 23;38(1):30.
Dabaghi GG, Rad MR, Mohammad-Zamani M, Shervedani AK, Bahrami-Samani F, Heshmat-Ghahdarijani K. The role of coenzyme Q10 as a preventive and therapeutic agent for the treatment of cancers. Current Problems in Cancer. 2024 Feb 1;48:101063.
Donisi I, Balestrieri A, Del Vecchio V, Bifulco G, Balestrieri ML, Campanile G, D’Onofrio N. l-Carnitine and Acetyl-l-Carnitine Induce Metabolism Alteration and Mitophagy-Related Cell Death in Colorectal Cancer Cells. Nutrients. 2025 Mar 13;17(6):1010.
Duraj T, Kalamian M, Zuccoli G, Maroon JC, D’Agostino DP, Scheck AC, Poff A, Winter SF, Hu J, Klement RJ, Hickson A. Clinical research framework proposal for ketogenic metabolic therapy in glioblastoma. BMC medicine. 2024 Dec 5;22(1):578.
Feng Y, Gao M, Xu X, Liu H, Lu K, Song Z, Yu J, Liu X, Han X, Li L, Qiu L. Elevated serum magnesium levels prompt favourable outcomes in cancer patients treated with immune checkpoint blockers. European Journal of Cancer. 2024 Dec 1;213:115069.
Fu A, Hou Y, Yu Z, Zhao Z, Liu Z. Healthy mitochondria inhibit the metastatic melanoma in lungs. International journal of biological sciences. 2019 Oct 15;15(12):2707.
Hanahan D. Hallmarks of cancer: new dimensions. Cancer discovery. 2022 Jan 1;12(1):31-46.
Kurgan N, Tsakiridis E, Kouvelioti R, Moore J, Klentrou P, Tsiani E. Inhibition of human lung cancer cell proliferation and survival by post-exercise serum is associated with the inhibition of Akt, mTOR, p70 S6K, and Erk1/2. Cancers. 2017 May 8;9(5):46.
Liang Z, Deng L, Zhou X, Zhang Z, Zhao W. Comprehensive Overview of Ketone Bodies in Cancer Metabolism: Mechanisms and Application. Biomedicines. 2025 Jan 16;13(1):210.
Min Z, Wang L, Jin J, Wang X, Zhu B, Chen H, Cheng Y. Pyrroloquinoline quinone induces cancer cell apoptosis via mitochondrial-dependent pathway and down-regulating cellular Bcl-2 protein expression. Journal of Cancer. 2014 Jul 29;5(7):609.
Park G, Haley JA, Le J, Jung SM, Fitzgibbons TP, Korobkina ED, Li H, Fluharty SM, Chen Q, Spinelli JB, Trivedi CM. Quantitative analysis of metabolic fluxes in brown fat and skeletal muscle during thermogenesis. Nature metabolism. 2023 Jul;5(7):1204-20.
Pieroth R, Paver S, Day S, Lammersfeld C. Folate and its impact on cancer risk. Current nutrition reports. 2018 Sep;7(3):70-84.
Poff AM, Ari C, Arnold P, Seyfried TN, D'agostino DP. Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer. International journal of cancer. 2014 Oct 1;135(7):1711-20.
Seki T, Yang Y, Sun X, Lim S, Xie S, Guo Z, Xiong W, Kuroda M, Sakaue H, Hosaka K, Jing X. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature. 2022 Aug 11;608(7922):421-8.
Seyfried TN. Cancer as a mitochondrial metabolic disease. Frontiers in cell and developmental biology. 2015 Jul 7;3:43.
Veech RL. The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins, leukotrienes and essential fatty acids. 2004 Mar 1;70(3):309-19.
Weir G, Ramage LE, Akyol M, Rhodes JK, Kyle CJ, Fletcher AM, Craven TH, Wakelin SJ, Drake AJ, Gregoriades ML, Ashton C. Substantial metabolic activity of human brown adipose tissue during warm conditions and cold-induced lipolysis of local triglycerides. Cell metabolism. 2018 Jun 5;27(6):1348-55.
Yang KL, Khoo BY, Ong MT, Yoong IC, Sreeramanan S. In vitro anti-breast cancer studies of LED red light therapy through autophagy. Breast Cancer. 2021 Jan;28(1):60-6.
Yau WW, Wong KA, Zhou J, Thimmukonda NK, Wu Y, Bay BH, Singh BK, Yen PM. Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue. IScience. 2021 May 21;24(5).
Yu Z, Hou Y, Zhou W, Zhao Z, Liu Z, Fu A. The effect of mitochondrial transplantation therapy from different gender on inhibiting cell proliferation of malignant melanoma. International journal of biological sciences. 2021 May 11;17(8).
Zhang P, Xiao Z, Xu H, Zhu X, Wang L, Huang D, Liang Y, Ni Q, Chen J, Yu X, Luo G. Hyperglycemia is associated with adverse prognosis in patients with pancreatic neuroendocrine neoplasms. Endocrine. 2022 Aug;77(2):262-71.
About the Author
Thomas P Seager, PhD is an Associate Professor in the School of Sustainable Engineering at Arizona State University. Seager co-founded the Morozko Forge ice bath company and is an expert in the use of ice baths for building metabolic and psychological resilience.
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