complex I

Complex I is located in the inner mitochondrial membrane and catalyzes the transfer of electrons from NADH to coenzyme Q (ubiquinone), reducing it to ubiquinol (QH2). This reaction is coupled to the translocation of 4 protons from the mitochondrial matrix to the intermembrane space, contributing to the proton-motive force used by ATP synthase (Complex V) to generate ATP. Complex I contains flavin mononucleotide (FMN) and multiple iron-sulfur (Fe-S) clusters that facilitate electron transfer. Clinically, Complex I dysfunction is implicated in mitochondrial diseases such as Leber hereditary optic neuropathy (LHON) and MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes), both often caused by mutations in mitochondrial DNA encoding Complex I subunits. Complex I is also a major site of reactive oxygen species (ROS) production due to electron leakage, contributing to oxidative stress and aging. Pharmacologically, rotenone (a pesticide) and metformin (used in diabetes) inhibit Complex I, the latter contributing to its mechanism of decreasing hepatic gluconeogenesis by lowering ATP/AMP ratio and activating AMPK. Complex I deficiency is the most common cause of mitochondrial respiratory chain disorders, often presenting in infancy or childhood with lactic acidosis, hypotonia, developmental delay, and encephalopathy (Leigh syndrome).