Complex I impairment in mitochondrial diseases and cancer: Parallel roads leading to different outcomes

Respiratory chain complex I (CI) dysfunctions have been recognized as one of the most frequent causes of mitochondrial neuro-muscular disorders. Moreover, latest reports reveal that CI impairment is a major contributing factor in many other pathological processes, including cancer. In fact, energy depletion, oxidative stress and metabolites unbalance are frequently associated with CI functional and structural alterations. The occurrence of mitochondrial DNA (mtDNA) mutations is a shared feature in neuro-muscular diseases and cancer; however, the two diverging phenotypes arise depending on the mutation type (disassembling versus non-disassembling mutations), the mutant load and the cytotype. In this review, we unify our knowledge on CI impairment caused by mutations in structural CI genes and assembly chaperones, both in mitochondrial disorders and cancer, stratifying such mutations based on their functional versus structural effects. We summarize shared and specific metabolic consequences of CI dysfunction in these pathologies, which allow us to draw two parallel roads that lead to different clinical outcomes. This article is part of a Directed Issue entitled: Bioenergetic dysfunction, adaptation and therapy.