Oxidative phosphorylation

Category: catabolism

Overview

Mitochondrial inner-membrane electron transport chain coupled to chemiosmotic ATP synthesis. Complex I (NADH:CoQ oxidoreductase) — NADH → CoQ; METFORMIN TARGET. Complex II (succinate dehydrogenase = TCA enzyme) — succinate → CoQ; doesn't pump protons. Complex III (CoQ:cytochrome c oxidoreductase) — Q-cycle pumps protons. Complex IV (cytochrome c oxidase) — final O2 reduction; CYANIDE + carbon monoxide target. Complex V (ATP synthase) — H+ flow drives ATP synthesis; OLIGOMYCIN target. Uncouplers (2,4-DNP historic, fatal hyperthermia) collapse the H+ gradient → heat instead of ATP. Mitochondrial myopathies / encephalopathies (MELAS, MERRF, LHON) arise from mutations in mtDNA-encoded ETC subunits.

Organ Systems

• endocrine
• musculoskeletal
• nervous

Pathway Steps

1. nadh → coenzyme-q10 — via Complex I (NADH:Q oxidoreductase) — METFORMIN target; pumps 4 H+. Complex I (NADH:ubiquinone oxidoreductase) pumps 4 H⁺ and is the largest ETC complex. It is a major site of superoxide generation and the target of metformin (partial inhibition raises AMP → AMPK) and rotenone.
2. succinate → coenzyme-q10 — via Complex II (= TCA succinate dehydrogenase); doesn't pump H+. Complex II is succinate dehydrogenase — the only ETC complex that does NOT pump protons — funnelling TCA-derived FADH₂ electrons into the ubiquinone pool, which is why FADH₂ ultimately yields less ATP than NADH.
3. coenzyme-q10 → cytochrome-c — via Complex III (Q-cycle); pumps 4 H+. Complex III runs the Q-cycle, pumping 4 H⁺ while passing electrons from ubiquinol to cytochrome c. It is the second major superoxide source and the target of antimycin A.
4. cytochrome-c → water — via Complex IV (cytochrome c oxidase) — CN/CO target; pumps 2 H+; final O2 reduction. Cytochrome c oxidase reduces O₂ to water (the terminal electron acceptor) and pumps 2 H⁺. It is irreversibly blocked by cyanide, carbon monoxide, azide, and H₂S at the heme-a₃/Cu_B center.
5. proton-gradient → atp — via Complex V (ATP synthase F1F0) — OLIGOMYCIN target. ATP synthase (F₁F₀) uses the proton-motive force to phosphorylate ADP (~3 ATP per rotation). Oligomycin blocks the F₀ proton channel; uncouplers (DNP, thermogenin/UCP1) dissipate the gradient as heat instead of ATP.

Known Modulators

• metformin (inhibitor) — Complex I (mild) — basis for hepatic gluconeogenesis suppression + lactic acidosis risk
• dichloroacetate (inhibitor) — pyruvate dehydrogenase kinase (PDK). DCA; lactic acidosis treatment + research metabolic-cancer indication; peripheral neuropathy
• trimetazidine (inhibitor) — long-chain 3-ketoacyl CoA thiolase (fatty acid oxidation block). 3-KAT inhibitor; shifts cardiac metabolism from FA to glucose; chronic stable angina (EU)
• nadh (substrate) — electron donor to complex I
• coq10 (cofactor) — ETC Complex I/II → III electron carrier (ubiquinone ↔ ubiquinol). Mobile lipid-soluble electron shuttle between Complex I/II and Complex III; supplemented to support mitochondrial energy in statin myopathy, mitochondrial disease, and aging.

References

• PMID 27775730