Increased Degradation Rates in the Components of the Mitochondrial Oxidative Phosphorylation Chain in the Cerebellum of Old Mice

Abstract

Brain structures differ in the magnitude of age-related neuron loss with the cerebellum being more affected. An underlying cause could be an age-related decline in mitochondrial bioenergetics. Successful aging of mitochondria reflects a balanced turnover of proteins involved in mitochondrial biogenesis and mitophagy. Thus, an imbalance in mitochondrial turnover can contribute to the diminution of cellular function seen during aging. Mitochondrial biogenesis and mitophagy are mediated by a set of proteins including MFN1, MFN2, OPA1, DRP1, FIS1 as well as DMN1l and DNM1, all of which are required for mitochondrial fission. Using N15 labeling, we report that the turnover rates for DMN1l and FIS1 go in opposite directions in the cerebellum of 22-month-old C57BL6j mice as compared to 3-month-old mice. Previous studies have reported decreased turnover rates for the mitochondrial respiratory complexes of aged rodents. In contrast, we found increased turnover rates for mitochondrial proteins of the oxidative phosphorylation chain in the aged mice as compared to young mice. Furthermore, the turnover rate of the components that are most affected by aging –complex III components (ubiquinol cytochrome C oxidoreductase) and complex IV components (cytochrome C oxidase)– was significantly increased in the senescent cerebellum. However, the turnover rates of proteins involved in mitophagy (i.e., the proteasomal and lysosomal degradation of damaged mitochondria) were not significantly altered with age. Overall, our results suggest that an age-related imbalance in the turnover rates of proteins involved in mitochondrial biogenesis and mitophagy (DMN1l, FIS1) in conjunction with an age-related imbalance in the turnover rates of proteins of the complexes III and IV of the electron transfer chain, might impair cerebellar mitochondrial bioenergetics in old mice.

Interspecies differences in proteome turnover kinetics are correlated with lifespans and energetic demands

“…The use of stable isotope labeling in conjunction with LC-MS/MS has opened the door for analyses of protein turnover kinetics on a global scale (4,9,17,18,29). In a number of model systems, proteomic studies have shown that aged individuals have significantly slowed protein turnover compared to younger counterparts (30)(31)(32), although this effect may not be universal and appears variable for different proteins, tissues and organisms (33)(34)(35)(36).…”

When nature’s robots go rogue: exploring protein homeostasis dysfunction and the implications for understanding human aging disease pathologies

“…One such ubiquitination target of Parkin is HIF-1, and Parkin expression was very recently shown to have an inverse correlation with both HIF-1 levels and metastasis in human breast cancer tissue [30]. As mentioned previously, with aging comes increased dysfunction in mitochondrial ETC proteins; imbalanced turnover has also been noted in proteins involved in the mitophagy process, for example in the mouse cerebellum [31] and aging skeletal muscle from several mammals [32]. An area of continued focus regarding the Parkin/PINK1 pathway are its roles in regulating basal mitophagy/proteostasis as opposed to activation only in response to a stress signal.…”

Brain Mitochondria, Aging, and Parkinson’s Disease

“…Popa-Wagner et al [ 62 ] have shown that the turnover rates for DMN1l and FIS1, which are proteins implicated in mitochondrial biogenesis, mitophagy, and fission go in opposite directions in the cerebellum of 22-month-old C57BL6j mice when compared to three-month-old mice. Unlike previous studies that have reported decreased turnover rates for the mitochondrial respiratory complexes of aged rodents, the authors found increased turnover rates for mitochondrial proteins of the oxidative phosphorylation chain in the aged mice when compared to young mice.…”