Mitochondrial respiration supports cancer growth independent of OXPHOS

Oxidative phosphorylation is a coordinated process yielding ATP, yet its constituent modules can operate autonomously and support oxygen-dependent, non-OXPHOS reactions that serve cellular proliferation, including neoplasia. Furthermore, even with oxygen present and ETC active, ATP synthesis requires surpassing defined thresholds; thus, respiration is not equivalent to phosphorylation. This review surveys mitochondrial pathways that use the ETC with oxygen as the terminal electron acceptor yet decouple respiration from ATP synthesis. These pathways support tumor progression by sustaining mechanistically distinct respiration-supported currencies, states, and signals, including oxidized coenzyme Q, matrix NAD⁺, mitochondrial membrane potential, transhydrogenase-derived NADPH, the downstream oxidizing capacity of the CIII-cytochrome c-CIV segment, and ROS as context-dependent outputs. These determinants shape de novo purine and pyrimidine biosynthesis, one‑carbon metabolism, shuttling of reducing equivalents, heme and FeS biogenesis, and proline, choline, and sulfide metabolism, revealing targetable nodes in the respiratory redox network. Therapeutic progress is expected from interventions that collapse the underlying infrastructure - particularly at the coenzyme Q-junction and the CIII-cytochrome c-CIV segment - rather than from strategies aimed solely at ATP deprivation.