Figure 1.

Overview of the main cellular and mitochondrial energy metabolism pathways. Mitochondrial metabolic pathways are fueled by glucose, fatty acids, and amino acids through respective catabolic processes to produce acetyl-CoA, a primary substrate for the TCA cycle, which is also recycled in the fatty acid β-oxidation (FAO) pathway producing NADH and FADH₂ reducing equivalents that feed the ETC CI and CII, respectively. Glucose undergoes glycolysis in the cytoplasm to form pyruvate which is converted into acetyl-CoA in mitochondria by the PDHC. Acetyl-CoA enters a series of enzyme-catalyzed reactions in the TCA cycle producing reduced forms of NADH and FADH₂ required for the transport of electrons to the ETC (the flow of electrons is illustrated by a grey dashed line). CI, CIII and CIV pump protons from the matrix to the IMS, generating a proton-motive force across the IMM, that drives the flux of protons back into the matrix via the ATP synthase to harness energy released in the form of ATP. The oxidation of NADH and FADH₂ via CI and CII replenishes the electron acceptors NAD+ and FAD to maintain TCA cycle activity. Fatty acids are imported into the mitochondria in the form of fatty-acyl-CoA via the carnitine shuttle system (CPT1 and CPT2) to enter the β-oxidation cyclic pathway. Initially, fatty acyl-CoAs undergo dehydrogenation resulting in a production of a FADH₂ reducing equivalent that transfers electrons to the electron transfer protein ETF and subsequently to the ubiquinone pool via the ETF ubiquinone oxidoreductase (ETF-QO), thus facilitating the entry of electrons to CIII. The remaining three catalytic steps involve hydration, second dehydrogenation during which NAD+ is reduced to NADH that is subsequently re-oxidized by CI, and thiolysis. In the final step, two carbons are removed from the fatty acyl-CoA ester, resulting in shortening of the entry product and its recycling via the FAO pathway. In addition, a molecule of acetyl-CoA is generated that contributes to the overall mitochondrial pool of acetyl-CoA used in the TCA cycle. Amino-acid degradation also contributes to the production of pyruvate, acetyl-CoA, or metabolic intermediates to be oxidized in TCA cycle. Abbreviations are as follows: CI: Complex I, CII: Complex II, CIII: Complex III, CIV: Complex IV, CV: Complex V, CoQ: coenzyme Q/ubiquinone, cyt c: cytochrome c, Acetyl-CoA: acetyl coenzyme A, PDHC: pyruvate dehydrogenase complex, CPT1/2: carnitine palmitoyltrasnferase 1/2, ETF: electron transfer flavoprotein, ETF-DH: ETF dehydrogenase, NADH: nicotinamide adenine nucleotide, FADH₂: flavin adenine dinucleotide, ADP: adenosine diphosphate, ATP: adenosine triphosphate.