Format

Send to

Choose Destination
See comment in PubMed Commons below
Cell. 2013 Dec 19;155(7):1624-38. doi: 10.1016/j.cell.2013.11.037.

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

Author information

1
Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Center for Neurosciences and Cell Biology, 3004-517 Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3004-517 Coimbra, Portugal.
2
Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Medical Oncology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney NSW 2052, Australia.
5
Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
6
Center for Neurosciences and Cell Biology, 3004-517 Coimbra, Portugal; Department of Life Sciences, Faculty of Science and Technology, University of Coimbra, 3004-517 Coimbra, Portugal.
7
Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
8
Center for Neurosciences and Cell Biology, 3004-517 Coimbra, Portugal; Department of Biology, University of Aveiro, 3810-193 Aveiro, Portugal.
9
Department of Biology, Massachusetts Institute of Technology, Paul F. Glenn Laboratory for the Science of Aging, Cambridge, MA 02139, USA.
10
Glenn Labs for the Biological Mechanisms of Aging, Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Department of Pharmacology, School of Medical Sciences, The University of New South Wales, Sydney NSW 2052, Australia. Electronic address: david_sinclair@hms.harvard.edu.

Abstract

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.

PMID:
24360282
PMCID:
PMC4076149
DOI:
10.1016/j.cell.2013.11.037
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center