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