Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal

被引：157

作者：

Burkewitz, Kristopher ^{[1
]}

Morantte, Ianessa ^{[1
]}

Weir, Heather J. M. ^{[1
]}

Yeo, Robin ^{[1
]}

Zhang, Yue ^{[1
]}

Huynh, Frank K. ^{[2
]}

Ilkayeva, Olga R. ^{[2
]}

Hirschey, Matthew D. ^{[2
]}

Grant, Ana R. ^{[3
]}

Mair, William B. ^{[1
]}

机构：

[1] Harvard Univ, Sch Publ Hlth, Dept Genet & Complex Dis, Boston, MA 02115 USA

[2] Duke Univ, Med Ctr, Duke Mol Physiol Inst, Durham, NC 27701 USA

[3] Univ Michigan, Sch Med, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

来源：

CELL | 2015年 / 160卷 / 05期

关键词：

DIETARY RESTRICTION; OXIDATIVE STRESS; PPAR-GAMMA; AMPK; NUTRIENT; CREB; LONGEVITY; CALCINEURIN; HEALTHSPAN; OCTOPAMINE;

D O I：

10.1016/j.cell.2015.02.004

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：

Low energy states delay aging in multiple species, yet mechanisms coordinating energetics and longevity across tissues remain poorly defined. The conserved energy sensor AMP-activated protein kinase (AMPK) and its corresponding phosphatase calcineurin modulate longevity via the CREB regulated transcriptional coactivator (CRTC)-1 in C. elegans. We show that CRTC-1 specifically uncouples AMPK/calcineurin-mediated effects on lifespan from pleiotropic side effects by reprogramming mitochondrial and metabolic function. This pro-longevity metabolic state is regulated cell nonautonomously by CRTC-1 in the nervous system. Neuronal CRTC-1/CREB regulates peripheral metabolism antagonistically with the functional PPAR alpha ortholog, NHR-49, drives mitochondrial fragmentation in distal tissues, and suppresses the effects of AMPK on systemic mitochondrial metabolism and longevity via a cell-nonautonomous catecholamine signal. These results demonstrate that while both local and distal mechanisms combine to modulate aging, distal regulation overrides local contribution. Targeting central perception of energetic state is therefore a potential strategy to promote healthy aging.

引用

页码：842 / 855

页数：14

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