CcO of CIV is the final enzyme in the respiratory electron transport chain, and CIV receives an electron from each of four cytochrome c (cyt c) molecules and transfers the electrons to oxygen molecules. Moreover, the reduced OCR in brain mitochondria isolated from middle-aged mice is accompanied by reduced cytochrome c oxidase (CcO) activity of CIV 8. These behavioral and histological alterations that occur during normal aging are similar to the characteristics of one of the most common neurodegenerative diseases, Parkinson’s disease (PD) 6, 7.
The reduced brain mitochondrial OCR in the middle-aged mice is accompanied by motor impairment, including reduced exploratory and voluntary motor activities, and an increased accumulation of phosphorylated α-synuclein in the motor cortex 5. We recently found that the earliest decline in mitochondrial function, which was assessed by measuring the mitochondrial oxygen consumption rate (OCR) of respiratory complex IV (CIV), appeared in the brains of 12- to 15-month-old (denoted as middle-aged) male mice during normal aging 4, 5. Mitochondrial function extends far beyond that of energy generation, because accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging 1 and many neurodegenerative diseases 2, 3. These results suggest that mitochondrial actin plays a crucial role in the regulation of the CcO activity and OCR of CIV with modification of the retention of cyt c between CIV and CIII. In contrast, no significant alteration in the assembly or the CcO activity of CIV in CIV-containing supercomplexes or CIV monomers was induced by CB. Actin was also associated with respiratory complex III (CIII) however, the amount of CIII-bound cyt c increased significantly after treatment of the mitochondria with CB. These changes were accompanied by a significant reduction in the amount of CIV-bound cytochrome c (cyt c). Inhibiting actin polymerization using cytochalasin B (CB) significantly enhanced the OCR and CcO activity of CIV in the mitochondria. To explore the mechanisms underlying the regulation of brain mitochondrial function, we examined CIV-associated proteins, and identified actin inside the isolated brain mitochondria. The oxygen consumption rate (OCR) and cytochrome c oxidase (CcO) activity of respiratory complex IV (CIV) in brain mitochondria significantly decline in middle-aged male mice compared to younger male mice.
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