Different mtDNA mutations modify tumor progression in dependence of the degree of respiratory complex I impairment

Abstract

Mitochondrial DNA mutations are currently investigated as modifying factors impinging on tumor growth and aggressiveness, having been found in virtually all cancer types and most commonly affecting genes encoding mitochondrial complex I (CI) subunits. However, it is still unclear whether they exert a pro- or anti-tumorigenic effect. We here analyzed the impact of three homoplasmic mtDNA mutations (m.3460G>A/MT-ND1, m.3571insC/MT-ND1 and m.3243A>G/MT-TL1) on osteosarcoma progression, chosen since they induce different degrees of oxidative phosphorylation impairment. In fact, the m.3460G>A/MT-ND1 mutation caused only a reduction in CI activity, whereas the m.3571insC/MT-ND1 and the m.3243A>G/MT-TL1 mutations induced a severe structural and functional CI alteration. As a consequence, this severe CI dysfunction determined an energetic defect associated with a compensatory increase in glycolytic metabolism and AMP-activated protein kinase activation. Osteosarcoma cells carrying such marked CI impairment displayed a reduced tumorigenic potential both in vitro and in vivo, when compared with cells with mild CI dysfunction, suggesting that mtDNA mutations may display diverse impact on tumorigenic potential depending on the type and severity of the resulting oxidative phosphorylation dysfunction. The modulation of tumor growth was independent from reactive oxygen species production but correlated with hypoxia-inducible factor 1α stabilization, indicating that structural and functional integrity of CI and oxidative phosphorylation are required for hypoxic adaptation and tumor progression.

Defects in mitochondrial metabolism and cancer

“…The contribution of CI mutations to cancer largely depends on the corresponding bioenergetics dysfunction that they cause. In fact, cancer cells affected by severe CI deficiency exhibited decreased tumorigenic potential both in vitro and in vivo , if compared to cells with a mild CI dysfunction [72] and CI activity is required for the induction of aerobic glycolysis in osteosarcoma cells [73]. In line with these finding, a recent study showed that intact CI activity is essential for cancer cell survival at low glucose levels, a condition commonly found in tumor microenvironment [74].…”

How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models

“…Data analysis by Larman et al showed that, across 5 different cancer types, displayed somatic mtDNA mutations ranging, from 13% in glioblastoma to 63% frequency in rectal adenocarcinomas [133]. Some data suggests that the effect of the somatic mtDNA mutations and the degree or nature of the tumorigenesis effect depend on the functional and threshold effect of the mutation [134][135][136]. For instance, the m.3460G>A/MT-ND1 mutation (decrease in complex I activity) result in different tumorigenic potential as determined by colony forming efficiency and tumor growth of osteosarcoma cybrids (cytoplasmic hybrids, Fig.…”

“…For instance, the m.3460G>A/MT-ND1 mutation (decrease in complex I activity) result in different tumorigenic potential as determined by colony forming efficiency and tumor growth of osteosarcoma cybrids (cytoplasmic hybrids, Fig. 2) [135] compared to the m.3571insC/MT-ND1 and the m.3243A>G/MT-TL1 mutation (severe structural and functional complex I alteration). More severe alterations in complex I (m.3571insC/MT-ND1 and the m.3243A>G/MT-TL1 mutation) resulted in a reduced tumorigenic potential both in vitro and in vivo, compared with cells displaying milder complex I dysfunction (m.3460G>A/MT-ND1 mutation) [135].…”

Mitochondrial genome instability in colorectal adenoma and adenocarcinoma

“…There is evidence that somatic mutations in mtDNA might play a role in cancer development [31,14,32]. Polyak et al [33] published the first paper describing somatic mtDNA mutations in colorectal cancer.…”

“…Statistical analysis revealed that fusion and fission (p= 0.0472) and mitochondrial localization genes subsets (p=0.0231) were more affected in adenocarcinoma samples. b Relative mtDNA copy number analysis showed a decreased number of mitochondrial genome content in adenocarcinoma when compared to normal colon (p=0.0092) mutated in tumors [39,32], and those mutations were associated with cancer progression mediated by ROS production, PI3K/Akt/PKC pathway activation, and HIF1α [14,13,31,40].…”