Cancer as a failed response to renegade mitochondria

Posted on August 28, 2025September 8, 2025Science

Department of Anesthesiology, State University of New York Downstate Health Sciences University, Brooklyn, NY 11203, USA

This article appeared in Experimental Cell Research, Volume 451, Issue 2 on 15 August, 2025.

Abstract

In 1948, before the word ‘mitochondrion’ gained common parlance in the lexicon of cell biologists, Cyril Darlington published The Plasmagene Theory of the Origin of Cancer without referring to mitochondria per se. Reconsideration of Darlington’s theory is warranted today because discoveries about the extraordinary capacities of mitochondria – the organelles that house Darlington’s “plasmagenes” – have grown exponentially.

If Darlington was right, if intracellular competition between mutant and wild-type mitochondria is the first cause of cancer, it may be the case that a general cure for cancer will include injection of: (A) nanoparticles carrying wild-type mitochondrial genes, and (B) copious amounts of wild-type mitochondria.

1. Introduction

Having discovered chromosomal crossover during meiosis and establishing himself as the cell biologist who would eventually be referred to as “The man who ‘invented’ the chromosome” (1), C.D. Darlington published his theory of the origin of cancer (2). The gist of Darlington’s hypothesis was that the initiating cause of cancer is a “mutation of self-propagating particles in the cytoplasm” that generates “competitive propagation” of those particles, with the nucleus “not itself directly responsible for what is going on.”

Confident in his understanding that Darwinian reproductive competition can occur in the cytoplasm of a single cell, but anxious about proposing such an all-encompassing proposition in reference to cancer, Darlington asked readers to “surrender certain established habits of reasoning, at least for the duration of the journey.” My own conjectures about cancer as a failed response to renegade mitochondria since 1982 did not cite Darlington’s Plasmagene Theory because I did not find his 1948 publication until 2025. Nevertheless, Darlington’s request for patience from readers also applies to those efforts (3-5), and to this review.

2. Apoptosis and Mitophagy

Just as apoptosis is the body’s way of ‘sculpting’ the nervous system by eliminating proto-neurons that do not make useful connections during embryo development, so apoptosis may be the procedure by which the body eliminates cells, like cancer cells, that threaten the level of cooperation between cells that is required to maintain multicellular organisms. If so, the reasonability of the hypothesis that competition between mutant and wild-type mitochondria is the first cause of cancer is augmented by the realization that mitochondria, having evolved from alpha-proteobacteria, have inherited the ability to hijack apoptosis (6,7) – and mutant mitochondria would gain a reproductive advantage by doing so in heteroplasmic cells if apoptosis is the primary nuclear response to a civil war in its cytoplasm (5).

Liberti and Locasale have explored possible reasons that “increased glucose uptake and fermentation of glucose to lactate” benefits cancer cells (8), but a hypothesis not examined is that nuclear genomes supplement ATP production through fermentation when mitochondria use too much of the ATP that they produce through oxidative phosphorylation for the purpose of competitive replication. An important benefit of accelerated glycolysis for mutant mitochondria is that it serves as an additional process for preventing apoptosis (9-13). Under this circumstance of augmented glycolysis, the dog is wagging its tail, but the dog is an OPEC-like cartel of renegade energy producers, while the tail is wild-type mitochondria and the nuclear genome.

Selective mitophagy would be a more elegant response to mutant mitochondria than apoptotic cell suicide, but recent evidence from Ikeda et al (14) indicates that mutant mitochondria can also hijack mitophagy, at least in T cells. As summarized by Diaz-Meco et al (15):

“Ikeda et al. demonstrate that cancer-cell mitochondria are progressively transferred to T cells, resulting in T cells losing their endogenous mitochondria. This process ultimately results in ‘homoplasmic replacement,’ where the T cells’ mitochondrial population becomes dominated by cancer-cell-derived mitochondria carrying mtDNA mutations … Replacing native mitochondria with dysfunctional [sic], cancer-derived counterparts renders T cells metabolically compromised. Indeed, Ikeda et al. report that these T cells display increased reactive oxygen species (ROS) production, heightened levels of senescence, and reduced expression of key activation markers, including PD-1 and CD69. Furthermore, these mitochondrial changes impair the ability of T cells to form long-lived memory cells, a critical component of sustained anti-tumor immunity. In vivo experiments in mouse models further corroborated these results, showing that T cells harboring cancer-derived mitochondria are less effective at mounting cytotoxic responses, ultimately contributing to tumor immune escape … This study finds that while native T cell mitochondria are highly sensitive to ROS-induced mitophagy, the mitochondria transferred from cancer cells resist this degradation.”

Further research is needed to determine whether “cancer-derived mitochondria” have additional targets for hijacking mitophagy.

3. Reversible Reaction

Cells approximately double their number of mitochondria before undergoing mitosis so that each daughter cell will receive a sufficient complement of mitochondria. If a doubling of mitochondria initiated by reproductive competition between mitochondria can trigger mitosis, instead of the doubling having been directed by nuclear DNA (i.e., if doubling mitochondria is a reversible reaction), repeating mitoses generated by ongoing competition between mitochondria in heteroplasmic daughter cells would look a lot like cancer (5). Or as put by Darlington, would “slowly or swiftly alter the character of the cell-lineage” (2) through what is now known as mito-nuclear crosstalk that remodels the nuclear genome (16). Adding the realization that “Mitochondria can shuttle between adjacent cells or travel to distant organs by breaking away from the parent cell and entering the circulation” (17, see also 18,19), mutant mitochondria could start “competitive propagation” in the cytoplasm of so many cells that at least one of them generates cancer.

4. Rolling the dice millions of times

Given about a quadrillion mitochondria in an animal the size of an adult human, mitochondrial mutations probably occur hundreds, if not thousands of times per day – mutations that are not corrected as usually happens with mutations in nuclear genomes, mutations that result in heteroplasmic cells many times per day, and account for much of the apoptosis that occurs every day. If so, myriad carcinogens (chemical, radiological, viral, etcetera) may not cause cancer directly, but instead impair the nuclear genome’s ability to accomplish the many-step process of apoptosis – thereby giving mutant mitochondria the time they need to acquire sufficient gain of function to “alter the character” (2) of their host cell’s nuclear DNA (16) and instigate repeating mitoses that drive dedifferentiation (3,5).

So, for example, the hypothesis here is that chronic myeloid leukemia is not caused directly by the Philadelphia chromosome abnormality that results in the formation of the BCR-ABL fusion gene. Instead, the Philadelphia chromosome abnormality and/or the BCR-ABL fusion gene interfere with apoptosis and impair the nuclear genome’s ability to accomplish that many-step process. And in cases where tyrosine kinase inhibitors target the BCR-ABL fusion gene to enable cancer remission, the elimination of the effect of the Philadelphia chromosome abnormality ‘corrects’ the mitochondrial abnormality by restoring the alacrity of apoptosis – by enabling the suicide, or ‘falling down’ (ptosis) of the cancerous cells.

Of course, the most carcinogenic entities could generate reproductively successful mitochondrial mutations in addition to causing nuclear mutations that impair apoptosis. And given 16,569 base pairs in the mitochondrial genome (20), a mutation at a single locus in one or a few genes, would not elicit an immune response that is analogous to cells’ reaction to bacteria, such that renegade mitochondria (3,5) probably have intracellular and intercellular immunity. That immunity would also be conferred upon free ranging mitochondria that circulate in blood, including mutant “ghost mitochondria” that land in good locations for generating metastases (21).

5. Evolution

How could such maladaptive phenomena evolve by natural selection? It is reasonable to think of mitochondrial capacities – especially their ability to purposively transfer between cells – as capacities that give renegade mitochondria agency during competition with wild-type mitochondria during oogenesis in female fetuses (3,5,22), and in subsequent ova that will contain ≈100,000 mitochondria (23) – enough mitochondria to supply rapidly mitosing cells in blastocysts – daughter cells that will not need to wait for mitochondria to replicate and over-fill their ATP tank before mitosing again.

Inter-cellular transfer abilities enable mitochondrial genes to evolve approximately ten times faster than nuclear genes. Indeed, mitochondria may approach viruses in terms of having a high evolutionary dynamic – a dynamic that gives them the ability to shift their status away from being the ultimate symbiont toward becoming parasitic when mutant mitochondrial transfers that would promote mitochondrial evolution in mid-trimester female fetuses, instead generate cancer in somatic cells (3,5). But those cancers would only be maladaptive for renegade mitochondria if/when they cause lethal cancer in females of reproductive age before those females reproduce – a sufficiently rare event to not counter the natural selection advantage that mutant mitochondria gain through transfer between haploid cells during oogenesis.

Competition between mitochondria during oogenesis produces some oocytes that are homoplasmic for renegade mitochondria and some oocytes that are homoplasmic for wild-type mitochondria, with heteroplasmic oocytes potentially shunted into polar bodies – such that there is no competition within the cytoplasm of either homoplasmic oocytes. Still, it stands to reason that individuals who suffer from heteroplasmy and maternally inherited mitochondrial diseases would have an increased risk of developing cancer (24-26).

6. Warburg Versus Weinhouse

Warburg and others have speculated that anaerobic glycolysis per se (27-29), instead of “Sequential mitoses at a radical rate” (3,5), coaxes cancer cells to dedifferentiate. However, incontrovertible evidence from Weinhouse contradicted the conclusion that anaerobic glycolysis is a response to inadequate production of ATP by aerobic glycolysis when “damaged” mitochondria are underproducing, which contradicted Warburg’s conclusion that anaerobic glycolysis is the initiating cause of cancer (30-32). Warburg’s abject defense of his “damaged mitochondria” conclusions, his ‘thou dost protest too much’ dismissal of Weinhouses’ work, was telling in that regard (33):

“Obviously, nothing could be less enlightened than the opinion of Weinhouse that respiration of cancer cells is as high, or even higher, than the respiration of normal growing cells.”

As put bluntly by Liberti and Locasale (8), “This phenomenon [the Warburg Effect] is observed even in the presence of completely functioning mitochondria” and normoxia.

7. Experiments

If intracellular competition between mutant and wild-type mitochondria is the first cause of cancer (2,3,5) and development of cancer is afforded by a failed response to mutant mitochondria via apoptosis (5), it may be the case that a general cure for cancer, and curtailment of metastases from established cancers, can be partially or completely accomplished by injection of: (A) nanoparticles carrying mitochondrial genes that are the wild-type analogues of mutated mitochondrial genes, and (B) copious amounts of wild-type mitochondria.

7.1 Step A

Nanoparticle transmission of genes is a promising and potentially less immunologically challenging alternative to gene therapy via viral transmission (34, e.g., 35-38).

Mitochondria use a limited codon orthography to translate proteins at mitoribosomes, but given the redundancy of the genetic code, that limited orthography can also be used by ribosomes in cytoplasm outside of mitochondria to make identical ‘wild-type’ proteins. Accordingly, nanoparticle delivery of genes using the limited codon orthography of wild-type mitochondria could generate simultaneous manufacture of wild-type proteins inside mitochondria and in their host cells’ cytoplasm outside of mitochondria.

7.2 Step B

The reasonability of infusing wild-type mitochondria, whether naked or incapsulated in extracellular vehicles (17), into the circulation of cancer patients is encouraged by the observation that introducing wild-type mitochondria into the cytoplasm of malignant cells reverses those cells’ oncogenic properties (16,39,40). The probability that stress in heteroplasmic cells generates “find me” signals to attract adjacent and circulating wild-type mitochondria (41) adds further encouragement, as do in vivo experiments and trials (42,43 and references therein). In that regard, an as yet unrecognized deleterious effect of chemotherapy and radiation therapy may be that they destroy noncancerous adjacent cells that would have been able to donate healthy wild-type mitochondria to cells where mutant and wild-type mitochondria are in competition.

Collecting sufficient wild-type mitochondria to flood the circulatory systems of cancer patients is a future challenge, but collecting enough wild-type mitochondria to flood the circulation of inbred laboratory rodents in whom cancer has been induced could be accomplished by isolating mitochondria from the tissue of maternally-related donors. If the mitochondria from donors are genetically identical to the wild-type mitochondria of recipients, and that proof-of-concept resolves early-stage cancer or curtails metastases from established cancers, the required volume of healthy mitochondria (17) needed for clinical trials could be produced by utilizing, at industrial scale, procedures described in section V of Liao and coauthors’ “Isolation of mitochondria from cells and tissues” (44). In a clinical setting, if the cancer has formed a discrete tumor, intraarterial injection upstream from the tumor might be most effective. If the cancer is not localized, has metastasized, is blood borne or lymphatic, intravenous injection combined with intralymphatic and bone marrow injection might be most propitious.

It is interesting to note that with few exceptions (e.g., cetaceans), mammalian mothers, including non-human primate mothers, eat their own afterbirth (45) while most humans discard afterbirth. If flooding the circulatory systems of cancer patients with wild-type mitochondria proves beneficial, perhaps mitochondria centrifuged from afterbirth and frozen in a trehalose solution (46) could serve as a natural source of wild-type mitochondria for human mothers’ future use, or be used by maternally related relatives.

8. Conclusion

The conjecture here, contrary to “certain established habits of reasoning” (2), is that mutated mitochondria in cancer cells are far from being ‘damaged’. Instead, they are competent (8), able to “hijack energy from immune cells” (47), evade endogenous immune responses (14,15), confer resistance to anticancer drugs (48), generate impunity from apoptosis (6,7,9-13), have intracellular and intercellular immunity (3,5), become self-serving as they draw upon genes from their bacterial heritage (6), initiate cancer through self-acquired gain of function that is facilitated by dedifferentiation (3,5), and start mito-nuclear crosstalk that remodels the nuclear genome (16).

Cells perceive bacteria to be a threat because bacteria are detected as foreign and they come from the outside, and like cells, we seldom perceive mitochondria as a threat because they are not foreign, and they live on the inside. Accordingly, a first-cause, fundamental understanding of cancer has been elusive because most cancer research has focused on the nuclear genome instead of focusing on the vastly more evolutionarily agile mitochondrial genome. Put more succinctly, the perspective here is that Darlington was right (2).

If steps A and B above are found to be salutary, cancer – The Emperor of All Maladies (49) – may be partially disrobed through nanoparticle genetic engineering and infusion of “enough healthy mitochondria” (17) to serve as reinforcements that will enable wild-type mitochondria to overwhelm mutant mitochondria. Whether steps A and B are useful or not, the final nail in the coffin of cancer could be a treatment that kills, or facilitates the apoptosis of, heteroplasmic cells. Indeed, given the extraordinary rate at which mitochondria mutate without correction, periodic elimination of “competitive propagation” between “self-propagating particles in the cytoplasm” (2) might prevent cancer and even serve as a cornerstone for the ever-elusive fountain of youth.

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Acknowledgement

I thank Professors Yiping Wang, Piotr Donizy and Janice L. Brissette for encouragement and advice, and James E. Cottrell and the Department of Anesthesiology at SUNY Downstate Medical Sciences University for encouragement and support.