The malate-aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast
The malate-aspartate NADH shuttle components are novel metabolic longevity regulators required for calorie restriction-mediated life span extension in yeast
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DOI：
10.1101/gad.1648308
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发表时间：
2008-04-01
影响因子：
10.5
通讯作者：
Lin, Su-Ju
中科院分区：
文献类型：
--
作者：
Easlon, Erin;Tsang, Felicia;Lin, Su-Ju
最近的研究表明，线粒体代谢的增加和伴随的NADH水平的降低介导热量限制（CR）诱导的寿命延长。线粒体内膜对NAD（烟酰胺腺嘌呤二核苷酸，氧化形式）和NADH是不可渗透的，目前还不清楚CR如何将线粒体代谢增加中继到位于空间上不同的隔室中的多个细胞途径。在这里，我们表明，线粒体组成部分的苹果酸-天冬氨酸NADH穿梭（Mdh 1 [苹果酸脱氢酶]和Aat 1 [天冬氨酸氨基转移酶]）和甘油-3-磷酸穿梭（Gut 2，甘油-3-磷酸脱氢酶）是新的长寿因素在酵母CR途径。过度表达Mdh 1、Aat 1和Gut 2可延长寿命，但不与CR协同作用。Mdh 1和Aat 1过度表达需要呼吸和Sir 2家族来延长寿命。mdh 1 Delta aat 1 Delta双突变阻断CR介导的寿命延长，并防止胞质/核池中NADH水平的特征性降低，表明苹果酸-天冬氨酸穿梭在CR下游靶点（如Sir 2）的激活中起主要作用。过表达的NADH穿梭也可以通过增加细胞的代谢适应性来延长寿命。总之，这些数据表明，CR可以通过激活NADH穿梭组件来延长寿命并改善与年龄相关的代谢疾病。
Recent studies suggest that increased mitochondrial metabolism and the concomitant decrease in NADH levels mediate calorie restriction (CR)-induced life span extension. The mitochondrial inner membrane is impermeable to NAD (nicotinamide adenine dinucleotide, oxidized form) and NADH, and it is unclear how CR relays increased mitochondrial metabolism to multiple cellular pathways that reside in spatially distinct compartments. Here we show that the mitochondrial components of the malate-aspartate NADH shuttle (Mdh1 [malate dehydrogenase] and Aat1 [aspartate amino transferase]) and the glycerol-3-phosphate shuttle (Gut2, glycerol-3-phosphate dehydrogenase) are novel longevity factors in the CR pathway in yeast. Overexpressing Mdh1, Aat1, and Gut2 extend life span and do not synergize with CR. Mdh1 and Aat1 overexpressions require both respiration and the Sir2 family to extend life span. The mdh1 Delta aat1 Delta double mutation blocks CR-mediated life span extension and also prevents the characteristic decrease in the NADH levels in the cytosolic/nuclear pool, suggesting that the malate-aspartate shuttle plays a major role in the activation of the downstream targets of CR such as Sir2. Overexpression of the NADH shuttles may also extend life span by increasing the metabolic fitness of the cells. Together, these data suggest that CR may extend life span and ameliorate age-associated metabolic diseases by activating components of the NADH shuttles.