Mitochondrial respiratory function is now recognized as a pivotal player in all the aspects of
cancer biology, from
tumorigenesis to aggressiveness and
chemotherapy resistance. Among the
enzymes that compose the respiratory chain, by contributing to energy production, redox equilibrium and oxidative stress, complex I assumes a central role. Complex I defects may arise from mutations in mitochondrial or nuclear
DNA, in both structural genes or assembly factors, from alteration of the expression levels of its subunits, or from drug exposure. Since
cancer cells have a high-energy demand and require macromolecules for proliferation, it is not surprising that severe complex I defects, caused either by mutations or treatment with specific inhibitors, prevent
tumor progression, while contributing to resistance to certain chemotherapeutic agents. On the other hand, enhanced oxidative stress due to mild complex I dysfunction drives an opposite phenotype, as it stimulates
cancer cell proliferation and invasiveness. We here review the current knowledge on the contribution of
respiratory complex I to
cancer biology, highlighting the double-edged role of this metabolic
enzyme in
tumor progression,
metastasis formation, and response to
chemotherapy.