--- module: 088-02 language: en chapter: 88 title: "Carbohydrate Metabolism, Bioenergetics, and Mitochondrial Integration" module_title: "Citric-acid cycle, electron transport, oxidative phosphorylation, and mitochondrial integration" source_sha256: 27e93ab806a541f887e0f522222487373f90ad23027b22f943d0aa7e1a3373ee --- # Citric-acid cycle, electron transport, mitochondria ## Mitochondrial structure and fuel entry ### Integrates ATP, biosynthesis, redox, heat, death ### Outer membrane porous via porins ### Inner membrane highly selective #### Cristae organise supercomplexes and synthase ### Matrix holds cycle enzymes and mtDNA ### Pyruvate carrier, then pyruvate dehydrogenase ### Acetyl-CoA also from fats and ketones #### Cannot cross inner membrane #### No net glucose: carbons lost as CO2 ## Citric-acid cycle reactions ### Citrate synthase condenses with oxaloacetate #### Thioester hydrolysis drives it #### Exported citrate carries acetyl units ### Aconitase has oxidant-sensitive iron-sulfur cluster ### Isocitrate dehydrogenase makes NADH, CO2 #### Activated by ADP and calcium #### Inhibited by ATP and NADH ### Alpha-ketoglutarate dehydrogenase #### Cofactors like pyruvate dehydrogenase #### Thiamine deficiency impairs both ### Succinyl-CoA synthetase ### Succinate dehydrogenase is complex two #### No proton pumping ### Malate dehydrogenase unfavourable #### Pulled by oxaloacetate consumption ### 3 NADH, 1 reduced flavin, 2 CO2 ## Biosynthetic branch points ### Citrate for lipids ### Alpha-ketoglutarate and others for amino acids ### Succinyl-CoA for haem ### Cataplerosis withdraws intermediates ### Anaplerosis refills them #### Pyruvate carboxylation, amino acids ### Depletion stalls cycle despite substrate ## Electron transport chain ### Complex one takes NADH electrons, pumps ### Complex two feeds ubiquinone without pumping ### Ubiquinol to complex three, pumps ### Cytochrome c carries one electron ### Complex four reduces oxygen to water, pumps ### No oxygen: carriers reduced, cycle slows #### Reliance on glycolytic lactate ## Oxidative phosphorylation and coupling ### Proton-motive force: voltage plus pH #### Matrix negative and alkaline ### Synthase rotor converts rotation to ATP ### Nucleotide translocase swaps ATP for ADP ### Low ADP raises gradient, slows respiration ### ATP use returns ADP, speeds transport #### Oxygen use reflects demand ## Shuttles and yield ### Cytosolic NADH cannot cross inner membrane ### Malate-aspartate shuttle to matrix NADH ### Glycerol-3-phosphate shuttle #### Less proton pumping ### About 2.5 ATP per NADH, 1.5 per flavin ### Glucose roughly 30 to 32 ATP #### Leak, transport, stoichiometry vary ## Uncoupling, inhibitors, oxidants ### Uncoupling: heat without ATP #### Uncoupling protein one activated by cold #### Chemical uncouplers: hyperthermia, acidosis #### Mild leak limits potential and ROS ### Rotenone complex one, antimycin three ### Cyanide and CO complex four #### CO also impairs haemoglobin transport ### Oligomycin blocks synthase proton channel ### Superoxide from complexes one and three #### Dismutase makes hydrogen peroxide #### Defence needs enzymes and compartments ## Calcium, genetics, dynamics, disease ### Calcium stimulates dehydrogenases #### Excess triggers permeability transition ### Outer-membrane permeabilisation releases cytochrome c #### Intrinsic apoptosis begins ### Mitochondrial DNA encodes a subset #### Maternal inheritance, heteroplasmy, thresholds #### High-demand tissues affected ### Fusion shares, fission segregates damage #### Mitophagy removes dysfunctional organelles ### Links to ER, peroxisomes, liver pathways ### Clues not individually diagnostic #### Biopsy, genetic, functional testing ### Energy failure alters redox and survival