Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging

被引：1295

作者：

Gomes, Ana P. ^{[1
,2
,3
]}

Price, Nathan L. ^{[1
]}

Ling, Alvin J. Y. ^{[1
]}

Moslehi, Javid J. ^{[4
,5
,6
]}

Montgomery, Magdalene K. ^{[7
]}

Rajman, Luis ^{[1
]}

White, James P. ^{[8
]}

Teodoro, Joao S. ^{[2
,3
]}

Wrann, Christiane D. ^{[8
]}

Hubbard, Basil P. ^{[1
]}

Mercken, Evi M. ^{[9
]}

Palmeira, Carlos M. ^{[2
,3
]}

de Cabo, Rafael ^{[9
]}

Rolo, Anabela P. ^{[2
,10
]}

Turner, Nigel ^{[7
]}

Bell, Eric L. ^{[11
]}

Sinclair, David A. ^{[1
,7
]}

机构：

[1] Harvard Univ, Sch Med, Dept Genet, Glenn Labs Biol Mech Aging, Boston, MA 02115 USA

[2] Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal

[3] Univ Coimbra, Fac Sci & Technol, Dept Life Sci, P-3004517 Coimbra, Portugal

[4] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med Oncol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Cardiovasc Med,Dept Med, Boston, MA 02115 USA

[7] Univ New S Wales, Sch Med Sci, Dept Pharmacol, Sydney, NSW 2052, Australia

[8] Harvard Univ, Sch Med, Dept Cell Biol, Dana Farber Canc Inst, Boston, MA 02115 USA

[9] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA

[10] Univ Aveiro, Dept Biol, P-3810193 Aveiro, Portugal

[11] MIT, Dept Biol, Paul F Glenn Lab Sci Aging, Cambridge, MA 02139 USA

来源：

CELL | 2013年 / 155卷 / 07期

基金：

澳大利亚研究理事会; 加拿大自然科学与工程研究理事会;

关键词：

CANCER-CELL METABOLISM; FATTY-ACID OXIDATION; GLUCOSE-HOMEOSTASIS; LIFE-SPAN; C-MYC; NICOTINAMIDE MONONUCLEOTIDE; CALORIE RESTRICTION; ENERGY-EXPENDITURE; DNA MUTATIONS; HYPOXIA;

D O I：

10.1016/j.cell.2013.11.037

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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-1 alpha/beta-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1 alpha 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-1 alpha/beta-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.

引用

页码：1624 / 1638

页数：15

共 55 条

[1]

Resveratrol improves health and survival of mice on a high-calorie diet [J].