｜ Mitochondrial energy metabolism and oxidative stress. Glycolysis metabolizes glucose to pyruvate which produces acetyl-CoA in the mitochondrial matrix for the TCA cycle. The TCA cycle can oxidize nutrients after a series of reactions to generate reducing equivalents for oxidative phosphorylation, including ETC composed of four complexes (CI-CIV) and F0F1-ATPase (CV) in the IMM. Complex I, III, and IV pump H + from the mitochondrial matrix to the intermembrane space along with the transport of electrons, forming MMP. The flux of H + back into the mitochondrial matrix is mostly mediated by F0F1-ATPase and drives ADP to synthesize ATP. O 2 •-is the primary ROS mainly generated through the leaking of superoxide at complexes I and III. O 2 •-is dismutated to H 2 O 2 by SOD2 and to GPx and catalase in the matrix and SOD1 in the intermembrane space. Created with BioRender.com. ADP: Adenosine diphosphate; ATP: adenosine triphosphate; ETC: electron transport chain; GPx: glutathione peroxidase; H 2 O 2 : hydrogen peroxide; IMM: inner mitochondrial membrane; MMP: mitochondrial membrane potential; O 2 •-: superoxide anion; SOD1/2: superoxide dismutase 1/2; TCA: tricarboxylic acid.

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... (Figure 1). The human brain needs high energy to continuously support healthy neuronal activity and cognition, and ATP is the most important energy source (Liesa and Shirihai, 2013). ...

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... TCA cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents like reduced nicotinamide adenine dinucleotide and flavine adenine dinucleotide for oxidative phosphorylation and critical metabolites for biosynthetic reactions (Arnold et al., 2022). Oxidative phosphorylation includes the ETC composed of four complexes (CI-CIV) and F0F1-ATPase (CV), and they are embedded in the inner mitochondrial membrane (IMM) together (Figure 1). Therefore, we can measure relevant enzymatic activities and intermediates to assess TCA and the mitochondrial respiratory chain. ...

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... antioxidant systems in cytoplasm and mitochondria are different. Manganese superoxide dismutase (MnSOD or SOD2) and classic glutathione peroxidase (Gpx1) are the primary antioxidant defenses in mitochondria, and other enzymes include CuZn-superoxide dismutase (CuZnSOD or SOD1), catalase, and phospholipid hydroperoxide glutathione peroxidase (Gpx4) (Figure 1; Yant et al., 2003;Van Remmen et al., 2004). ...

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... transport can be assessed by observing the percentage of mitochondrial distribution of soma, axons, and other regions in neurons by using TEM similar to that described above (Pickett et al., 2018). www.nrronline.org ...