Cellular Adaptations to Oxidative Phosphorylation Defects in Cancer

Mitochondrial DNA (mtDNA) somatic mutations or mutations in nuclear genes encoding mitochondrial proteins important for the assembly, activity, or maintenance of the individual oxidative phosphorylation (OXPHOS) complexes have been observed in tumors. Although the functional consequence of such mutations is unclear at the moment, retrograde signaling in response to OXPHOS defects can activate various nuclear genes and signaling pathways that alter mitochondrial function, tumor invasion, metastasis, redox-sensitive pathways, programmed cell death pathways, calcium signaling pathways, and cellular pathways leading to global changes in cellular morphology and architecture. In addition, we have found that some cancer cell lines harboring deleterious mtDNA mutations upregulate the expression of members of the peroxisome-proliferator activated coactivator 1 family of coactivators, probably to sustain the necessary ATP production for cell proliferation. In this chapter, we describe such cellular adaptations and changes in response to OXPHOS defects that are associated with a variety of cancer cell types.