Overview Function couple energy stored in electron acceptors (NADH, FADH2) to ATP synthesis process called oxidative phosphorylation 3 ATPs per NADH NADH enters mitochondria from production in cytosol via malate-aspartate shuttle glycerol-3-phosphate shuttle 2 ATPs per FADH2 lower energy content than NADH Pathway located in inner mitochondrial membrane series of carrier enzymes NADH and FADH2 create a proton gradient across the inner membrane pass electrons in a stepwise fashion oxygen is the final electron acceptor flow of proton back down concentration gradient drives F0F1 ATP synthase complex net production of ATP Clinical importance electron transport inhibitors disrupt membrane bound carrier enzymes result ↓ proton gradient ↓ ATP synthesis ↓ O2 consumption ↑ intracellular NADH/NAD+ ratio CO source combustion (smoking, fires, car exhaust, grills) paint strippers presentation pulse oximeter may read 100% sat but actually O2 sat is ↓ pulse oximeters will read both the CO and O2 as saturating hemoglobin patients exposed to CO must use a co-oximeter (that also detects carboxyhemoglobin) cherry-red lips and cheeks headache/nausea tachypnea tachycardia treatment 100% O2 CN source nitroprusside administration byproduct give with thiosulfate to consume produced CN combustion of polyurethane burning furniture, mattresses Mining (gold), metal extraction presentation seizures, tachypnea, tachycardia, headache, flushing treatment sodium thiosulfate forms thiocyanate, less-toxic metabolite, renally excreted nitrites convert hemoglobin to methemoglobin (ferrous to ferric) does not allow cyanide transport to mitochondria must be given shortly after exposure note: victims of house fires may have both CO and CN poisoning ATPase inhibitors directly inhibit mitochondrial ATP synthase result ↑ proton gradient no ATP is produced because electron transport stops e.g. oligomycin uncoupling agents "uncouples" ATP production from the proton gradient ↑ permeability of membrane result ↓ proton gradient ↑ O2, NADH consumption ATP synthesis stops, but electron transport continues produces heat examples 2,4-DNP aspirin/salicylates fevers often occur after aspirin overdose thermogenin in brown fat UCP protein generates heat for newborns Compound Site of inhibition CO (carbon monoxide) Cytochrome c CN (cyanide) Cytochrome c Antimycin Cytochrome b/c1 Doxorubicin CoQ Rotenone (pesticide) NADH dehydrogenase