Oxidative phosphorylation complexes I and V (OXPHOS complexes I and V)

Oxidative phosphorylation (OXPHOS) complexes I and V are essential components of the mitochondrial energy production system. Complex I, also known as NADH:ubiquinone oxidoreductase, is the first and largest enzyme of the electron transport chain, where it oxidizes NADH and pumps protons to generate a transmembrane electrochemical gradient [1.1.2, 1.3.1]. Complex V, or ATP synthase, utilizes this gradient to drive the synthesis of ATP from ADP and inorganic phosphate [1.3.3, 1.3.5]. These complexes have emerged as significant therapeutic targets in oncology, as many aggressive and treatment-resistant tumors rely heavily on OXPHOS for metabolic requirements [1.3.2, 1.2.4]. Drugs such as metformin and the clinical-stage inhibitor IACS-010759 target Complex I, while agents like gboxin inhibit Complex V to induce an energy crisis in cancer cells [1.2.2, 1.5.5]. However, targeting these complexes presents substantial challenges, including a narrow therapeutic index and risks of severe side effects like lactic acidosis and neurotoxicity due to the inhibition of vital bioenergetic pathways in healthy tissues [1.2.3, 1.5.5]. Additionally, certain drugs like sertraline have been shown to inhibit both complexes as an off-target effect, contributing to mitochondrial toxicity [1.4.1].

Other names

NADH:ubiquinone oxidoreductase and ATP synthaseMitochondrial respiratory chain complexes I and VComplex I and Complex VNADH dehydrogenase and F1Fo-ATP synthase

Inhibition of the mitochondrial electron transport chain at Complex I and the phosphorylation of ADP at Complex V, leading to ATP depletion and metabolic reprogramming.