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

Publication ,  Journal Article
Gomes, AP; Price, NL; Ling, AJY; Moslehi, JJ; Montgomery, MK; Rajman, L; White, JP; Teodoro, JS; Wrann, CD; Hubbard, BP; Mercken, EM; Rolo, AP ...
Published in: Cell
December 19, 2013

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.

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Published In

Cell

DOI

EISSN

1097-4172

Publication Date

December 19, 2013

Volume

155

Issue

7

Start / End Page

1624 / 1638

Location

United States

Related Subject Headings

  • Transcription Factors
  • Sirtuin 1
  • Reactive Oxygen Species
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Oxidative Phosphorylation
  • NAD
  • Muscle, Skeletal
  • Mitochondria
  • Mice
  • Hypoxia-Inducible Factor 1, alpha Subunit
 

Citation

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Gomes, A. P., Price, N. L., Ling, A. J. Y., Moslehi, J. J., Montgomery, M. K., Rajman, L., … Sinclair, D. A. (2013). Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 155(7), 1624–1638. https://doi.org/10.1016/j.cell.2013.11.037
Gomes, Ana P., Nathan L. Price, Alvin J. Y. Ling, Javid J. Moslehi, Magdalene K. Montgomery, Luis Rajman, James P. White, et al. “Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.Cell 155, no. 7 (December 19, 2013): 1624–38. https://doi.org/10.1016/j.cell.2013.11.037.
Gomes AP, Price NL, Ling AJY, Moslehi JJ, Montgomery MK, Rajman L, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013 Dec 19;155(7):1624–38.
Gomes, Ana P., et al. “Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.Cell, vol. 155, no. 7, Dec. 2013, pp. 1624–38. Pubmed, doi:10.1016/j.cell.2013.11.037.
Gomes AP, Price NL, Ling AJY, 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. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013 Dec 19;155(7):1624–1638.
Journal cover image

Published In

Cell

DOI

EISSN

1097-4172

Publication Date

December 19, 2013

Volume

155

Issue

7

Start / End Page

1624 / 1638

Location

United States

Related Subject Headings

  • Transcription Factors
  • Sirtuin 1
  • Reactive Oxygen Species
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Oxidative Phosphorylation
  • NAD
  • Muscle, Skeletal
  • Mitochondria
  • Mice
  • Hypoxia-Inducible Factor 1, alpha Subunit