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Carbohydrates and fats are metabolized through the mitochondrial intermediate acetyl-CoA, by the tricarboxylic acid (TCA) cycle and β-oxidation pathways. These pathways strip the reducing equivalents off of the hydrocarbons and transfer them to mitochondrial NAD+ and FAD. The resulting reducing equivalents (electrons) are transferred from NADH + H+ and FADH2 to complexes I and II, respectively, initiating the electron transport chain (ETC). From complexes I and II, the electrons are transferred to coenzyme Q (CoQ) and then through complex III, cytochrome c, and complex IV to reduce 1/2 O2 into H2O. The energy that is released as the electrons pass through complexes I, III, and IV is used to transport protons out across the mitochondrial inner membrane to generate a trans-inner membrane electrochemical potential (∆P = ∆ψ + ∆μH+). The energy stored in this capacitance, ∆P, can then be used by the ATP synthase, complex V, to condense ADP + Pi to ATP, the ATP being exported to the cytosol by the adenine nucleotide translocators (ANTs). ∆P can also be used to drive many other functions including the import of cytosolic Ca2+ into the mitochondrial matrix (Wallace, 2005, 2007; Wallace et al., 2010).

If excess electrons accumulate in complexes I and III and CoQ, they can be donated directly to O2 to give superoxide anion (O2.–), a potent oxidizing agent. Mitochondrial O2.– can be converted to hydrogen peroxide (H2O2) by the matrix Mn superoxide dismutase (MnSOD) or the intermembrane space Cu/ZnSOD. The H2O2 can acquire an additional electron, producing the highly reactive hydroxyl radical (·OH), or can be reduced to water by glutathione peroxidase. Consequently, the core ROS species (O2.–, H2O2, and ·OH) are primarily of mitochondrial origin (Wallace, 2005, 2007; Wallace et al., 2010).

The mitochondrion also incorporates a self-destruct system, the mitochondrial permeability transition pore (mtPTP). The mtPTP can be activated by a decline in either ∆P or high-energy phosphates or an increase in mitochondrial matrix Ca2+ level or ROS toxicity.

The efficiency by which OXPHOS generates ATP is called the coupling efficiency. This is determined by the efficiency with which complexes I, III, and IV convert the oxidation of reducing equivalents into ∆P and the efficiency by which complex V converts ∆P into ATP. A tightly coupled OXPHOS system maximizes ATP generation per calorie burned. A less coupled system must burn more calories for the same amount of ATP, resulting in a higher caloric intake and greater heat production (Wallace, 2007).

All of the proton translocating complexes of OXPHOS (complexes I, III, IV, and V) must be balanced to ensure that one complex is not disproportionately permeable to protons and thus shorts ∆P. This is achieved by having the core electron and proton transport genes retained on a single piece of nonrecombining DNA, the exclusively maternally inher-



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