Chapter 24: Oxidative Phosphorylation and Mitochondrial Function

The electron transport chain, a series of protein complexes anchored in the inner mitochondrial membrane, accepts electrons from the reduced cofactors NADH and FADH2, which are produced during earlier stages of cellular respiration. These electrons are sequentially transferred through complexes I, II, III, and IV, with each transfer releasing energy that pumps protons from the mitochondrial matrix into the intermembrane space. This creates an electrochemical gradient, or proton motive force, that serves as the energy source for ATP synthase. The ATP synthase enzyme harnesses the flow of protons back into the matrix to phosphorylate adenosine diphosphate into ATP, with approximately 2.5 ATP molecules produced per NADH molecule and 1.5 per FADH2 molecule. The chapter explains the chemiosmotic mechanism, describing how electron transfer couples directly to phosphorylation through this proton gradient rather than through high-energy chemical intermediates. Key structural and functional components are examined, including the iron-sulfur clusters in complex I, the flavin adenine dinucleotide cofactor in complex II, coenzyme Q as an electron shuttle, the cytochrome proteins in complex III, and the copper and iron-containing active site of cytochrome oxidase. The chapter also addresses NADH shuttle systems, which transfer reducing equivalents across the mitochondrial membrane since NADH itself cannot cross the membrane directly. Clinical applications emphasize how disruptions to oxidative phosphorylation cause severe metabolic consequences: ischemia-reperfusion injury depletes ATP and triggers cell death, thyroid hormone excess increases proton leak and heat production, antiretroviral medications cause mitochondrial DNA depletion, chemotherapy drugs inhibit complex III, and genetic mutations in mitochondrial or nuclear DNA produce degenerative diseases characterized by impaired energy production and lactic acidosis. The chapter concludes by connecting oxidative phosphorylation to cellular survival, thermogenesis, and the pathogenesis of numerous metabolic and genetic disorders.