Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.

Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA
Cell. 2013 155 (7): 1624-38

PMID: 24360282 · PMCID: PMC4076149 · DOI:10.1016/j.cell.2013.11.037

Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.

Copyright © 2013 Elsevier Inc. All rights reserved.

MeSH Terms (14)

Aging AMP-Activated Protein Kinases Animals Cell Nucleus Hypoxia-Inducible Factor 1, alpha Subunit Mice Mitochondria Muscle, Skeletal NAD Oxidative Phosphorylation Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Reactive Oxygen Species Sirtuin 1 Transcription Factors

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