Mitochondrial electron transport chain and iron-sulfur cluster-containing proteins (ETC/Fe-S proteins)

The mitochondrial electron transport chain (ETC) is a fundamental metabolic pathway composed of four primary protein complexes (Complexes I-IV) located in the inner mitochondrial membrane (PMID: 28112728). Iron-sulfur (Fe-S) clusters are essential inorganic cofactors embedded within these complexes that facilitate the precise transfer of electrons required for oxidative phosphorylation (UniProt: P00338). This system is the primary driver of cellular ATP production and plays a pivotal role in maintaining redox balance and initiating apoptosis (PMID: 23699526). In various cancers, the ETC is exploited to meet high metabolic demands, making it a target for small-molecule inhibitors like IACS-010759, which specifically targets Complex I (PMID: 29892070). Additionally, dysfunction in Fe-S cluster biogenesis or ETC subunits is a hallmark of several mitochondrial and neurodegenerative diseases (PMID: 24121362). However, the ubiquitous nature of these proteins across all aerobic tissues presents significant challenges for drug development, particularly regarding the risk of systemic metabolic toxicity and lactic acidosis (PMID: 30104711).

Other names

Oxidative phosphorylation systemOXPHOSMitochondrial respiratory chainElectron transport systemMitochondrial complexes I-IV

Inhibition of electron transfer within mitochondrial complexes, leading to the disruption of the proton gradient, depletion of intracellular ATP, and induction of oxidative stress.