Journal
AGING CELL
Volume 18, Issue 5, Pages -Publisher
WILEY
DOI: 10.1111/acel.12999
Keywords
caloric restriction; lipid metabolism; longevity; mitochondria; NAD; PGC-1a; redox metabolism
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Funding
- NIA NIH HHS [T32 AG000213, RF1 AG057408, R01 AG037000] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007665] Funding Source: Medline
- NIGMS NIH HHS [R01 GM065386, R25 GM083252] Funding Source: Medline
- BLRD VA [I01 BX003846] Funding Source: Medline
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Deleterious changes in energy metabolism have been linked to aging and disease vulnerability, while activation of mitochondrial pathways has been linked to delayed aging by caloric restriction (CR). The basis for these associations is poorly understood, and the scope of impact of mitochondrial activation on cellular function has yet to be defined. Here, we show that mitochondrial regulator PGC-1a is induced by CR in multiple tissues, and at the cellular level, CR-like activation of PGC-1a impacts a network that integrates mitochondrial status with metabolism and growth parameters. Transcriptional profiling reveals that diverse functions, including immune pathways, growth, structure, and macromolecule homeostasis, are responsive to PGC-1a. Mechanistically, these changes in gene expression were linked to chromatin remodeling and RNA processing. Metabolic changes implicated in the transcriptional data were confirmed functionally including shifts in NAD metabolism, lipid metabolism, and membrane lipid composition. Delayed cellular proliferation, altered cytoskeleton, and attenuated growth signaling through post-transcriptional and post-translational mechanisms were also identified as outcomes of PGC-1a-directed mitochondrial activation. Furthermore, in vivo in tissues from a genetically heterogeneous mouse population, endogenous PGC-1a expression was correlated with this same metabolism and growth network. These data show that small changes in metabolism have broad consequences that arguably would profoundly alter cell function. We suggest that this PGC-1a sensitive network may be the basis for the association between mitochondrial function and aging where small deficiencies precipitate loss of function across a spectrum of cellular activities.
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