Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.
Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.
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DOI：
10.1016/j.cell.2013.11.037
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发表时间：
2013-12-19
期刊：
影响因子：
64.5
通讯作者：
Sinclair DA
中科院分区：
文献类型：
--
作者：
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
自从真核生物包含线粒体的细菌祖先以来，核和线粒体基因组必须密切协调它们的活动，因为它们各自编码氧化磷酸化（OXPHOS）系统的不同亚基。线粒体功能障碍是衰老的标志，但其原因仍有争议。我们表明，在衰老过程中，有一个特定的损失线粒体，但不是核，编码OXPHOS亚基。我们将原因追溯到核-线粒体通讯的替代PGC-1α/β-独立途径，该途径由核NAD+下降和常氧条件下HIF-1α积累诱导，与瓦尔堡重编程相似。删除SIRT 1加速了这一过程，而提高老年小鼠的NAD+水平则以SIRT 1依赖的方式恢复了年轻小鼠的线粒体功能。因此，破坏PGC-1α/β非依赖性核-线粒体通讯的假缺氧状态有助于线粒体功能随年龄的下降，这一过程显然是可逆的。
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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影响因子：
64.8
作者：
Burnett, Camilla;Valentini, Sara;Cabreiro, Filipe;Goss, Martin;Somogyvari, Milan;Piper, Matthew D.;Hoddinott, Matthew;Sutphin, George L.;Leko, Vid;McElwee, Joshua J.;Vazquez-Manrique, Rafael P.;Orfila, Anne-Marie;Ackerman, Daniel;Au, Catherine;Vinti, Giovanna;Riesen, Michele;Howard, Ken;Neri, Christian;Bedalov, Antonio;Kaeberlein, Matt;Soti, Csaba;Partridge, Linda;Gems, David
通讯作者：
Gems, David
DOI：
10.1101/sqb.2012.76.010439
发表时间：
2011
期刊：
Cold Spring Harbor symposia on quantitative biology
影响因子：
--
作者：
Cantó C;Auwerx J
通讯作者：
Auwerx J
影响因子：
3.9
作者：
Kwong, LK;Sohal, RS
通讯作者：
Sohal, RS
影响因子：
7.1
作者：
Fernandez-Marcos, Pablo J.;Auwerx, Johan
通讯作者：
Auwerx, Johan
DOI：
10.1146/annurev.pathol.4.110807.092250
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Haigis MC;Sinclair DA
通讯作者：
Sinclair DA