Oxidative Phosphorylation and the Electron Transport Chain
Concept Name
Oxidative Phosphorylation
Genetic Loci
MT‑ND1, MT‑ND2 (Complex I); MT‑CYB (Complex III); MT‑CO1, MT‑CO2 (Complex IV); MT‑ATP6 (Complex V). Mitochondrial DNA mutations in these genes cause Leber’s hereditary optic neuropathy (LHON) and MELAS.
Intracellular Cascade
Proton gradient (ΔpH and Δψ) created by Complexes I, III, and IV drives ATP synthase (Complex V) via the binding‑change mechanism. Uncoupling proteins (UCP1 in brown fat) dissipate the gradient to generate heat.
Required Cofactors
Iron‑sulfur clusters (Fe‑S), copper (Complex IV), FMN, FAD, heme groups (cytochromes). Coenzyme Q (ubiquinone) is synthesized from tyrosine and cholesterol.
Histology Stains
Gomori trichrome stain reveals “ragged‑red fibers” in mitochondrial myopathies. COX (cytochrome c oxidase) staining shows patchy deficiency in mitochondrial disorders.
EM Findings
Abnormal mitochondria with paracrystalline inclusions are seen in mitochondrial myopathies. Subsarcolemmal accumulation of mitochondria appears as ragged‑red fibers on modified Gomori trichrome.
Knockout Phenotype
Knockout of NDUFS4 (Complex I subunit) in mice causes Leigh‑like syndrome with progressive neurodegeneration and early death. Tissue‑specific knockout in dopaminergic neurons leads to Parkinsonism.
Specific Toxins
Cyanide (CN⁻) inhibits Complex IV (cytochrome c oxidase). Rotenone inhibits Complex I. Oligomycin inhibits ATP synthase. Carbon monoxide competes with oxygen for Complex IV.