Oxidative phosphorylation pathway (OXPHOS) (OXPHOS)

Oxidative phosphorylation (OXPHOS) is the metabolic pathway through which cells utilize enzymes to oxidize nutrients, releasing energy to form adenosine triphosphate (ATP) within the mitochondria [1.1.1]. This process occurs in the inner mitochondrial membrane and involves the electron transport chain (ETC), consisting of complexes I through IV, and ATP synthase (complex V) [1.1.3, 1.1.4]. While many tumors rely on glycolysis, certain cancers and cancer stem cells exhibit a high dependency on OXPHOS for energy and survival, making it a critical therapeutic target in oncology [1.1.2, 1.1.3]. Drugs such as metformin, atovaquone, and IACS-010759 target this pathway by inhibiting specific ETC complexes, thereby depleting cellular ATP and inducing oxidative stress [1.1.3, 1.2.4, 1.3.1]. Beyond cancer, OXPHOS dysfunction is central to neurodegenerative disorders like Parkinson's and Alzheimer's diseases, as well as metabolic and cardiovascular conditions [1.1.1, 1.4.2]. However, the clinical application of OXPHOS inhibitors is often limited by a narrow therapeutic window and significant safety concerns, most notably lactic acidosis and neurotoxicity [1.2.4, 1.2.5].

Other names

Mitochondrial energy metabolismElectron transport chainMitochondrial respirationAerobic respirationMitochondrial oxidative phosphorylation

Inhibition of the mitochondrial electron transport chain (ETC) complexes (I-IV) or ATP synthase (Complex V), leading to ATP depletion, increased reactive oxygen species (ROS) production, and metabolic stress [1.1.3, 1.2.4, 1.3.1].