ETC

**Note:** "ETC" is most commonly the electron transport chain on USMLE. It is occasionally used for other things, such as "et cetera". Tell me if you meant something else.

**Location:** Inner mitochondrial membrane (cristae).

**Components and flow of electrons:** - **Complex I (NADH dehydrogenase / NADH-CoQ oxidoreductase):** accepts electrons from NADH, passes them to ubiquinone (CoQ), and pumps 4 H+. - **Complex II (succinate dehydrogenase):** part of the TCA cycle. It accepts electrons from FADH2 (succinate to fumarate) and passes them to CoQ. It does NOT pump H+, which is why FADH2 yields less ATP than NADH. - **CoQ (ubiquinone):** a mobile lipid-soluble carrier. - **Complex III (cytochrome bc1 / CoQ-cytochrome c oxidoreductase):** passes electrons to cytochrome c and pumps 4 H+. - **Cytochrome c:** a mobile carrier in the intermembrane space. Its release into the cytosol triggers apoptosis (via caspase-9/apoptosome). - **Complex IV (cytochrome c oxidase, a/a3):** transfers electrons to O2, forming H2O, and pumps 2 H+. Oxygen is the final electron acceptor. - **Complex V (ATP synthase, F0F1):** protons flow back down their gradient through F0, driving ATP synthesis by F1 (about 4 H+ per ATP).

**Chemiosmotic coupling:** Electron flow creates a proton-motive force (the H+ gradient across the inner membrane). ATP synthase uses it to make ATP from ADP + Pi.

**Inhibitors (high-yield):** - **Complex I:** rotenone, amytal (barbiturate), MPP+ (the toxic metabolite of MPTP, which causes parkinsonism), metformin (in part). - **Complex III:** antimycin A. - **Complex IV:** cyanide, carbon monoxide, azide, H2S. Cyanide poisoning gives a bitter almond odor, cherry-red skin, and lactic acidosis. Treatment is hydroxocobalamin, or sodium nitrite plus sodium thiosulfate. - **Complex V (ATP synthase):** oligomycin. This blocks the proton flow, so the gradient builds up and electron transport slows or stops.

**Uncouplers:** These make the inner membrane leaky to H+, so the gradient dissipates and energy is lost as heat. ATP synthesis falls, O2 consumption rises, and the ETC runs faster. - 2,4-dinitrophenol (DNP): causes hyperthermia. - Aspirin overdose (salicylates): hyperthermia, tinnitus, and mixed respiratory alkalosis/anion gap metabolic acidosis. - **Thermogenin (UCP-1):** physiologic uncoupling in brown fat, important in neonates for non-shivering thermogenesis.

**Clinical correlations:** - **Mitochondrial myopathies (e.g., MELAS, MERRF, Leber hereditary optic neuropathy):** defects in oxidative phosphorylation genes cause lactic acidosis, muscle weakness, and neurologic findings. They show maternal (mitochondrial) inheritance with heteroplasmy, and ragged red fibers on Gomori trichrome stain. - **Reactive oxygen species (ROS):** electrons leaking from Complexes I and III form superoxide, which is relevant to aging and ischemia-reperfusion injury. - **Tissues with high ETC dependence:** brain, heart, and skeletal muscle are the most affected by ETC dysfunction.

**Mnemonic for inhibitors:** "Rotenone (I), Antimycin (III), Cyanide/CO (IV), Oligomycin (V)."