November 2025

The Mitochondrion: Beyond ATP Synthesis

Joseph Corsini, Ph.D. and Julie Alessandra, MTE

Evolutionary History of the Mitochondrion: At some point probably around 2.7 billion years ago two cells, a primitive bacterium called Rickettsia and another cell entered into a mutualistic relationship that generated the incredible diversity of multi-celled life visible to us today on earth. The bacterium eventually gave up most of its genetic material by transferring it to the nuclear genome of the host cell, becoming the mitochondrion that we find in modern plant, animal, and protist cells. The origins of the mitochondrion and chloroplast are discussed at length by Nick Lane in the popular science book, The Vital Question (Lane 2025). In animals, the mitochondrion generates most of the chemical energy needed by cell, primarily in the form of adenosine triphosphate (ATP), which is in turn used by many enzyme reactions in the cell. Today the animal mitochondrion genome (chromosome) contains only 13 protein coding genes and all of the transfer RNA genes (see Zardoya 2020 and Rackham & Filipovska 2022 for reviews of the mitochondrial genome), with all of the other thousand or so proteins required for mitochondrial function encoded in the nuclear chromosomes. Amongst the mitochondrial proteins encoded in the nucleus are most of the protein subunits of the electron transport chain complexes and the ATP synthase. These electron carrier complexes and the ATP synthase work in concert to generate large quantities of ATP for the cell.

Functions of the mitochondrion: While ATP synthesis is an important duty of the mitochondrion, it has other important roles in cellular function. These roles are varied, ranging from maintaining Calcium homeostasis to melatonin synthesis. Pregnenolone, the precursor to all steroid hormones (such as testosterone and estrogen), is synthesized in mitochondria in sync with the daily circadian cycles, as seen in cultured human glioma cells and in mouse brains (Witzig et al 2020), and mitochondria are known to monitor levels of toxic reactive oxygen species and heavy metals as well as aid with the DNA damage control and intrinsic cell suicide pathways that are activated when the body needs to eliminate an unhealthy cell. Stress signals from the endoplasmic reticulum (ER) will also stimulate apoptosis (cell suicide) through the mitochondrial regulator CDIP1 which in turn triggers the BAX-controlled apoptosis pathway (apoptosis is cell suicide - discussed in Friedman and Nunnari 2014). Mitochondrial stress responses are complex and there is continuous cross-talk between the nucleus and the mitochondrion. One of the lines of communication is through the nuclear transcription factor NRF2, a protein that controls many aspects of mitochondrial stress physiology including biogenesis, response to reactive oxygen species, ATP synthesis, and membrane potential (discussed by Tan et al 2017 and Panieri et al 2022). These authors describe in detail the ways that NRF2 in the nucleus both influences the mitochondrion and is influenced by the mitochondrion in a variety of stress conditions. The mitochondrion is also involved in inflammatory responses that occur in response to infectious disease agents or metabolic conditions such as non-alcoholic fatty liver disease, and the activation of the inflammasome (a large protein complex that forms in cells in response inflammatory signals) is known to be linked to mitochondrial dysfunction. These inflammatory processes in the cell lead to membrane disruption and decrease in respiratory chain function through the BAK-BAX pore systems and a variety of other pathways. (reviewed in Marchi et al 2023). Altogether, the mitochondrion engages in at least fourteen pathways that intersect with various aspects of basic cellular functioning (pregnenolone synthesis, ATP synthesis, inflammasome assembly, reactive oxygen species (ROS) production and sensing, Calcium balance, DNA damage detection and cell suicide, heavy metal sensing, proton leaking processes, maintaining membrane potentials, communicating with the ER and nucleus, biogenesis, mitophagy, and endogenous melatonin synthesis).  And this list is very likely incomplete. Finally, it is worth pointing out that the complex interconnections between the nucleus, the cell membrane, the endoplasmic reticulum, and the mitochondrion suggests that, in some cases, instances of mitochondrial dysfunctions that manifest in the mitochondrion itself could have their origins in metabolic/mutational disturbances elsewhere in the cell, including the nucleus. 

Mitochondrial Dysfunction and Health: Mitochondrial dysfunction has been detected in a variety of health conditions, including heart disease and neurological disorders like Parkinson’s and Alzheimer’s, although the causal links for most remain speculative in their details (discussed in Cheng et al 2021; Federico et al 2021). Srivastava (2017) discusses the free radical ‘theory’ of aging (really a hypothesis) and refers to research suggesting that mitochondrial dysfunction increases with age. Rodent studies examining at least some of the functions (ATP synthesis, membrane potential, oxygen consumption, ROS production) have shown that mitochondrial function is adversely affected by stress (reviewed in Martin et al 2018, who note that related human studies of this phenomenon have not been well-controlled). Zong et al (2024) review what is known about the relationship between mitochondria and a variety of diseases. They also describe a long list of supplements that are known from pre-clinical studies to affect some of the functional parameters in mitochondria - the long-awaited development of rapid assays for multiple mitochondrial functions will tell us more about the clinical efficacy of these supplements.1, 2 The connection between mitochondrial dysfunction and artificial light is also under investigation, and  accumulating evidence suggests that mitochondria function best when the body is regularly exposed to natural light rather than artificial light (Arranz-Paraiso et al 2023; Rajput et al 2023; Witzig et al 2020; Tan et al 2017).

Mitochondrial Dysfunction and Cancer: The role of mitochondrial dysfunction in cancer has been investigated extensively in cultured cells; many of these studies are discussed and referenced in Proietti et al 2017, Luo et al 2020, and Guerra-Librero et al 2021). For example, Lunova et al (2020) experimented with near infrared light in three human liver cancer lines, finding that two of them were killed by the experimental exposure and one of them was unaffected. In order to pinpoint the cause of cytotoxicity, the authors examined lysosomal, endoplasmic reticulum, and mitochondrial function, finding that the light conditions that influenced mitochondrial function did not affect endoplasmic reticulum or lysosomal function and that altered mitochondrial function was correlated with cell death. Other examples studying NIR effects in cancer cells can be found in our NIR bulletin. Some work has been done liquid tumors by Nelson et al (2021), who collected tumor samples from, human patients with and without leukemia (liquid tumors are easy to collect from the blood), finding among other things, that oxidative phosphorylation (synthesis of ATP using the electron transport chain) was disrupted in cancerous leukocytes, and that restoration of this process was toxic to the tumor cells. Proietti et al (2017) describe experimental work with cultured cells showing that the balance between glycolytic and oxidative ATP synthesis (uses the electron transport chain) has a bearing on the degree of malignancy. Zhao et al (2022) point out that many cancer stem cells have a metabolic phenotype that is skewed toward oxidative phosphorylation (electron transport), and discuss the relationship between the mode of ATP production and responses to various cancer treatment regimes.  It is clear now that cancers individually have varying capacity for oxidative phosphorylation, with some cancers producing ATP primarily through chemiosmotic mechanisms (electron transport, oxidative phosphorylation) and some primarily using glycolysis (and consequently lactate dehydrogenase to regenerate NAD+).  Many are also intermediate, generating significant amounts of ATP with both pathways. This body of work suggests that, at least in some cases, shifting cancer cells from a primarily glycolytic to a more oxidative metabolism can reactivate the normal stress pathways and induce apoptosis (cell suicide). Note that an important inductive corollary to this observation is that we would expect (hypothesize) that fully functioning mitochondria will block transformation processes leading to cancer.

The mutational landscape of the tumor cell DNA (both mitochondrial and nuclear) is relevant to the relationship between mitochondria and cancer. Luo et al (2020) review the variety of mutations found in nuclear and mitochondrial genes from cancer cells. These include inactivating mutations in nuclear genes that encode Kreb’s cycle enzymes and respiratory chain proteins, as well as in mitochondrial genes encoding tRNA’s, rRNA’s, and respiratory chain proteins such as complex I protein ND2. Kopinski et al (2021) and Baysal (2006) also discuss the relationship between cancer and mutations in genes encoding key mitochondrial proteins. Note that in humans, the question of timing as well as ultimate cause and effect relationships between these mutations and the transformation process is not always simple – in other words, we know that the mutations are present and relevant in the final observed cancer phenotype, but we don’t know if they were the initial cause of the transformation process.

There has also been long-standing interest in the effects of deuterium (an isotope of hydrogen that occurs naturally at low levels) on the mitochondrion and its relation to cancer. People encounter unnaturally high concentrations of deuterium through tap water and the consumption of foods that are not locally sourced or available in the local environment (concentrations are higher in tropical and high-carbohydrate foods (Basov et al 2015)). A recent publication by Yaglova et al (2023) reviews what is known about the effects of deuterium on biological systems. They point out that deuterium interferes with the ATP synthase in the mitochondrion, as well as with some of the electron transport proteins. The link between deuterium and cancer has also been investigated in cultured cells, mouse models, and human trials (Syroshkin et al 2019). Yaglov et al (2023) cite studies showing that deuterium depleted or enriched water has cytotoxic effects on cultured tumor cells (these seemingly contradictory effects have yet to be explained). Nude mouse trials with transplantable human tumors show significant effects of administering deuterated water (reviewed in Syroeshkin et al 2019). There have been some small-scale clinical trials that suggest significant positive effects with deuterium depleted water, with only one of them randomized (noted in Lu and Chen 2024); the results suggest a dramatic effect of deuterium depletion on prostate tumor mass (Kovacs 2011). 

Summary: Mitochondrial dysfunction is observed in a number of degenerative disease states, including cancer, that have no known cures. We also know from studies in rodent and cell culture that essential functions such as pregnenolone synthesis, mitochondrial turnover, modulation of reactive oxygen species, and mitochondrial mitophagy/biogenesis are tied to circadian rhythms that require exposure to natural light (Witzig et al 2020; Tan et al 2017) as well as avoidance of artificial light. A large body of work also shows that there are clearly connections between mitochondrial dysfunction and transformation processes that lead to cancer, and that modulating mitochondrial function has potential in cancer treatment regimes. In addition, exercise is also known, in humans and in animal models, to stimulate mitophagy and mitogenesis (a function of healthy mitochondria) at least partially through the generation of reactive oxygen species (for examples see Chen et al 2018, Porter et al 2015, and reviewed in Memme et al 2021). All in all, it seems reasonable to expect that lifestyle interventions including avoidance of non-native EMF’s and modern artificial light (see our technical bulletins describing natural light therapy and EMF’s), regular exercise, and frequent exposure to natural sunlight will have positive effects on mitochondrial and overall metabolic health. These interventions, while important during cancer therapy, are expected to be most effective in preventing initial occurrence of cancer as well as in preventing a recurrence of cancer after a primary recovery period.

1-Zong and colleagues also review mitochondrial dysfunction and comment upon the possible involvement of such dysfunction in metabolic disease and other disorders. While they present a large body of evidence supporting the notion that mitochondrial function is disrupted in numerous disease states, they remain careful in their analysis, stating very clearly, for example, that the relationship between mitochondrial dysfunction and metabolic disorder is, at this point, only suggestive and that the road from bench to bedside has been “fraught” with difficulty. They are referring  to the fact that, as discussed in the footnote below, there are no systematic, non-invasive ways to assay for any one of the mitochondrial functions, let alone all of them.

2- There are three primary reasons for the inability to easily detect mitochondrial outcomes directly in patients. First, as described above, mitochondrial 'function' is not a single phenomenon that can be measured by a single test. Each functional assay (ATP synthesis, reactive oxygen species output, Calcium balance, DNA damage detection and cell suicide, heavy metal sensing, proton leaking processes, maintaining membrane potentials, communicating with the ER and nucleus, biogenesis, mitophagy) requires its own set of reagents or specialized equipment and requires its own sample. Second, these tiny structures, barely visible in a light microscope, in general can only be studied by killing the cells that host them. Those techniques which do not require killing the cell still require that the living cell be removed from its home tissue. This means that tissue samples (biopsies) must be removed from the tissue of interest, requiring invasive procedures and sedation for most tissues in the body. Because of these combined issues, as well as others, there are no standardized methods for assessing mitochondrial function (some of these issues are discussed by Brand and Nichols in their 2011 report). This means that although we might have good reason to think that certain interventions might improve overall mitochondrial functionality, it is very difficult to actually measure this in a human patient to determine efficacy of a given intervention.  The third reason is the fact that in situations where mitochondrial function can be ascertained, it is not usually possible to determine whether the mitochondrial dysfunction led to the disease state or whether the disease state led to the mitochondrial dysfunction. Despite the preceding issues and as discussed above, there are some fundamental aspects of mitochondrial dysfunction that have been established and lead us strongly suspect that some interventions will have a positive effect on disease outcomes. 

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