Mitochondrial electron transport chain and cellular ATP synthesis pathways (ETC/OXPHOS)

The mitochondrial electron transport chain (ETC) and cellular ATP synthesis pathways, collectively known as oxidative phosphorylation (OXPHOS), are the primary energy-generating systems in eukaryotic cells [1]. Located in the inner mitochondrial membrane, the ETC consists of four multi-protein complexes (I-IV) and two mobile electron carriers (ubiquinone and cytochrome c) that facilitate the transfer of electrons from NADH and FADH2 to molecular oxygen [2]. This process creates a proton gradient across the membrane, which drives ATP synthase (Complex V) to produce ATP from ADP and inorganic phosphate [1]. Beyond energy production, these pathways are critical for maintaining cellular redox balance and regulating apoptosis through the release of cytochrome c [4]. Dysregulation of these pathways is central to various pathologies, including primary mitochondrial diseases like Leigh syndrome, neurodegenerative disorders such as Parkinson's disease, and metabolic syndromes [5]. In oncology, certain cancers exhibit a dependency on OXPHOS for survival and resistance to therapy, leading to the development of inhibitors like IACS-010759 [4]. However, because these pathways are essential for the function of almost all tissues, particularly the heart and brain, targeting them requires high specificity to avoid systemic toxicity and life-threatening lactic acidosis [3].

Other names

Oxidative phosphorylationOXPHOSRespiratory chainMitochondrial respiratory chainElectron transport chain

Inhibition of electron transfer within mitochondrial complexes I-IV or inhibition of ATP synthase (Complex V), leading to the disruption of the proton motive force and reduction in cellular ATP production.