Figure 1
(a) Fundamental aspects of mitochondrial function. Caloric energy (carbohydrates and fats) is converted into molecular (ATP) and thermal (heat, energy lost during electron transport) energy and oxidants (reactive oxygen species (ROS)). While ATP is utilized for energy requiring cell functions, mitochondrial generated ROS influence redox cell signaling processes, including induction of nuclear gene expression (via redox sensitive transcription factors), which contribute to cell function. Differences in mtDNA sequences are proposed to influence mitochondrial oxygen utilization (economy) and ROS production that impact cell function. The conversion of caloric energy into these respective components is dependent on overall organelle economy (influenced by the mtDNA-encoded subunits), degree of positive or negative energy balance, and uncoupling proteins. ATP and ROS are utilized for cellular functions (energy requiring processes and redox signaling); mitochondrial ROS also serve as a means for communication to the nuclear compartment and regulation of certain nuclear genes. (b) Carbohydrates are metabolized to glucose that is further converted to pyruvate (glycolysis) in the cytoplasm and transported into the mitochondrion. Acetyl CoA is formed from pyruvate via oxidative decarboxylation (pyruvate dehydrogenase), where it enters the citric acid cycle that yields reducing equivalents (NADH and FADH2) for electron transport located within the mitochondrial inner membrane. NADH is oxidized at complex I (NADH:coenzyme Q oxidoreductase or NADH dehydrogenase) of the transport chain while FADH is oxidized at complex II (succinate:coenzyme Q oxidoreductase or succinate dehydrogenase, part of the citric acid cycle). Electrons are next passed to coenzyme Q (Q). Complex III (coenzyme Q:cytochrome c oxidoreductase or cytochrome bc1 complex) passes electrons from reduced coenzyme Q (Q) to cytochrome c (c), a peripheral membrane protein that alternately binds cytochrome c1 (of complex III) and to complex IV (cytochrome c oxidase). Complex IV catalyzes the one electron oxidations of four consecutive reduced cytochrome c molecules and the concomitant four electron reduction of one O2 molecule to yield H2O. During electron transport, protons are pumped across the inner membrane from the matrix into the intermembrane space, creating an electrochemical gradient. The free energy resulting from this gradient is utilized to condense a molecule of inorganic phosphate (Pi) with ADP at complex V (ATP synthase or F1F0—ATPase) to yield ATP. ATP is subsequently transported out of the matrix by the inner membrane bound adenine nucleotide translocase (ANT) with the exchange of ADP. Fats bypass glycolytic metabolism in the cytoplasm and undergo β-oxidation in the mitochondrion to yield acetyl CoA (plus NADH and FADH2 per cycle of oxidation), which enters the citric acid cycle to generate substrates for electron transport. During electron transport, superoxide (O2.−) is generated when electrons are added to O2; O2.− is converted to hydrogen peroxide (H2O2) in the mitochondrion by manganese superoxide dismutase (MnSOD or SOD2). H2O2 (which is freely diffusible) can participate in cell signaling processes (H2O2 levels are regulated by a number of antioxidants within the mitochondrion and the cell, not illustrated). Alternatively, O2.− reacts with nitric oxide (.NO) to form peroxynitrite (ONOO−), an oxidant, which in the presence of carbon dioxide (CO2) forms nitrosoperoxycarbonate (ONOOCO2−), a nitrating agent.
