Relevance of Mitochondrial Genetics and Metabolism in Cancer Development

Abstract

Cancer cells are characterized in general by a decrease of mitochondrial respiration and oxidative phosphorylation, together with a strong enhancement of glycolysis, the so-called Warburg effect. The decrease of mitochondrial activity in cancer cells may have multiple reasons, related either to the input of reducing equivalents to the electron transfer chain or to direct alterations of the mitochondrial respiratory complexes. In some cases, the depression of respiratory activity is clearly the consequence of disruptive mitochondrial DNA (mtDNA) mutations and leads as a consequence to enhanced generation of reactive oxygen species (ROS). By acting both as mutagens and cellular mitogens, ROS may contribute directly to cancer progression. On the basis of our experimental evidence, we suggest a deep implication of the supercomplex organization of the respiratory chain as a missing link between oxidative stress, energy failure, and tumorigenesis. We speculate that under conditions of oxidative stress, a dissociation of mitochondrial supercomplexes occurs, with destabilization of complex I and secondary enhanced generation of ROS, thus leading to a vicious circle amplifying mitochondrial dysfunction. An excellent model to dissect the role of pathogenic, disassembling mtDNA mutations in tumor progression and their contribution to the metabolic reprogramming of cancer cells (glycolysis vs. respiration) is provided by an often underdiagnosed subset of tumors, namely, the oncocytomas, characterized by disruptive mutations of mtDNA, especially of complex I subunits. Such mutations almost completely abolish complex I activity, which slows down the Krebs cycle, favoring a high ratio of aketoglutarate/succinate and consequent destabilization of hypoxia inducible factor 1a (HIF1a). On the other hand, if complex I is partially defective, the levels of NAD þ may be sufficient to implement the Krebs cycle with higher levels of intermediates that stabilize HIF1a, thus favoring tumor malignancy. The threshold model we propose, based on the population-like dynamics of mitochondrial genetics (heteroplasmy vs. homoplasmy), implies that below threshold complex I is present and functioning correctly, thus favoring tumor growth, whereas above threshold, when complex I is not assembled, tumor growth is arrested. We have therefore termed "oncojanus" the mtDNA genes whose disruptive mutations have such a double-edged effect.

Systemic Activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila melanogaster

“…Deregulation of mitochondrial metabolism and function is associated with a number of both inherited and acquired human disorders, including but not limited to type 2 diabetes, neurodegenerative disorders, and tumorigenesis (32,33). Consequently, therapeutic interventions that can restore or increase mitochondrial activity are thought to be essential for our ability to treat these complex and often debilitating diseases (32).…”

Intra-individual purifying selection on mitochondrial DNA variants during human oogenesis

“…region is a mutational hotspot. This high rate of synonymous MT-ND5 variants are not totally a surprise given the high rate of heteroplasmic alleles in MT-ND5 also found in blood samples (Just et al, 2015) and in oncocytic tumors (Gasparre et al, 2007(Gasparre et al, , 2013.…”

“…Given this background, intra-individual selective pressure may play an important role in enabling the mitochondrial genome to preserve information. For example, this seems to occur during the shift from heteroplasmy to homoplasmy of inherited and somatic mtDNA mutations affecting the function of respiratory complex I in oncocytic tumors (Gasparre et al, 2009(Gasparre et al, , 2013. On the other hand, the existence of an ovarian selection system that would eliminate deleterious mtDNA mutations during oocyte maturation is still debated (Wallace, 2013).…”

Additional cytosine inside mitochondrial C-tract D-loop as a progression risk factor in oral precancer cases

“…Due to their role on control of cell death, mitochondria have been implicated in tumorigenesis. 4,6 Since mitochondrial DNA mutations in OSCC were first described, 9 today we know that changes in Mitochondrial DNA (mtDNA) include addition and small & large scale deletions in oral tumors and surrounding tissues. 10e13 Most of the mutations reported have been in the Dloop region, which is a hypervariable non-coding region.…”