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

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. Osteosarcomacells carryingsuchmarkedCI impairment displayed a reduced tumorigenic potential both in vitroandin vivo, whencompared with cells with mild CI dysfunction, suggesting thatmtDNAmutations 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 1a stabilization, indicating that structural and functional integrity of CI and oxidative phosphorylation are required for hypoxic adaptation and tumor progression.1