Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C-elegans
Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C-elegans
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DOI：
10.1038/nature08466
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发表时间：
2009-10-08
期刊：
影响因子：
64.8
通讯作者：
Tavernarakis, Nektarios
中科院分区：
文献类型：
--
作者：
Artal-Sanz, Marta;Tavernarakis, Nektarios
细胞能量代谢的显著变化是衰老过程的普遍标志（1）。线粒体是真核细胞中产生能量的细胞器，其生物起源和功能是决定寿命的主要因素。线粒体活性的遗传或药理学操作深刻地影响着不同生物体的寿命（2）。然而，在衰老过程中调节线粒体生物发生和能量代谢的分子机制知之甚少。抑制蛋白是普遍存在的、进化上保守的蛋白质，其在线粒体内膜形成环状高分子量复合物（3）。在这里，我们表明，线粒体prohibitin复合物促进长寿的调节线粒体功能和脂肪代谢的线虫秀丽隐杆线虫。我们发现，prohibitin缺乏会缩短野生型动物的寿命。值得注意的是，在滞育突变体中或在饮食限制的条件下，抑制素的敲低促进长寿。此外，抑制素缺乏延长了线粒体功能或脂肪代谢受损的动物的寿命。抑制素的耗尽以遗传背景和年龄特异性方式影响ATP水平、动物脂肪含量和线粒体增殖。总之，这些发现揭示了一种调节线粒体生物发生和功能的新机制，对C.优雅的在哺乳动物衰老过程中，抑制素可能在调节能量代谢方面具有类似的关键作用。
Marked alterations in cellular energy metabolism are a universal hallmark of the ageing process(1). The biogenesis and function of mitochondria, the energy-generating organelles in eukaryotic cells, are primary longevity determinants. Genetic or pharmacological manipulations of mitochondrial activity profoundly affect the life-span of diverse organisms(2). However, the molecular mechanisms regulating mitochondrial biogenesis and energy metabolism during ageing are poorly understood. Prohibitins are ubiquitous, evolutionarily conserved proteins, which form a ring-like, high-molecular-mass complex at the inner membrane of mitochondria(3). Here, we show that the mitochondrial prohibitin complex promotes longevity by modulating mitochondrial function and fat metabolism in the nematode Caenorhabditis elegans. We found that prohibitin deficiency shortens the lifespan of otherwise wild-type animals. Notably, knockdown of prohibitin promotes longevity in diapause mutants or under conditions of dietary restriction. In addition, prohibitin deficiency extends the lifespan of animals with compromised mitochondrial function or fat metabolism. Depletion of prohibitin influences ATP levels, animal fat content and mitochondrial proliferation in a genetic-background- and age-specific manner. Together, these findings reveal a novel mechanism regulating mitochondrial biogenesis and function, with opposing effects on energy metabolism, fat utilization and ageing in C. elegans. Prohibitin may have a similar key role in modulating energy metabolism during ageing in mammals.