Mitochondrial respiratory chain complex I and complex III (CI & CIII)

Mitochondrial respiratory chain complexes I and III are integral components of the oxidative phosphorylation (OXPHOS) system located within the inner mitochondrial membrane. Complex I, or NADH:ubiquinone oxidoreductase, is the entry point for electrons from NADH, facilitating their transfer to ubiquinone while pumping protons into the intermembrane space (StatPearls NBK539811). Complex III, known as the cytochrome bc1 complex, continues the electron flow by transferring electrons from ubiquinol to cytochrome c, further contributing to the proton motive force required for ATP synthesis (UniProt P00156). These complexes are essential for cellular energy homeostasis, but they are also primary sites for the generation of reactive oxygen species (ROS), which can lead to oxidative stress and cellular damage. Mutations in the subunits of these complexes are associated with severe mitochondrial diseases such as Leigh syndrome and Leber hereditary optic neuropathy (NIH GARD). In pharmacology, Complex I is a well-known target of the antidiabetic drug metformin, which mildly inhibits the complex to activate AMPK signaling and improve insulin sensitivity (PubMed 11015186). Conversely, Complex III is targeted by antimicrobial agents like atovaquone to disrupt energy metabolism in pathogens and is being explored as a target in oncology to starve high-energy cancer cells (PubChem CID 2274).

Other names

NADH:ubiquinone oxidoreductase (Complex I)Ubiquinol-cytochrome c reductase (Complex III)Cytochrome bc1 complexElectron transport chain complexes I and IIIOXPHOS complexes I and III

Inhibition of electron transfer within the respiratory chain, leading to a reduction in the mitochondrial proton gradient, decreased ATP production, and modulation of downstream metabolic signaling pathways (e.g., AMPK activation).