Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers.
Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers.
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DOI：
10.18632/aging.100943
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Cohen P
中科院分区：
文献类型：
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作者：
Cobb LJ;Lee C;Xiao J;Yen K;Wong RG;Nakamura HK;Mehta HH;Gao Q;Ashur C;Huffman DM;Wan J;Muzumdar R;Barzilai N;Cohen P
线粒体在衰老和衰老相关疾病的发病机制中起着关键作用。最近的线粒体转录组分析显示，存在由线粒体DNA(MtDNA)转录的多个小mRNAs。人蛋白(HN)是一种编码于线粒体DNA 16S核糖体RNA区域的多肽，是一种神经保护因子。在电子计算机上的搜索发现，在线粒体DNA中与人蛋白相同的区域还有6个额外的多肽；我们将这些多肽命名为小的人蛋白样多肽(SHLP)。我们确定了这些多肽的功能作用和潜在的作用机制。SHLP在体外调节细胞活力的能力不同。我们重点研究了SHLP2和SHLP3，因为它们与HN具有相似的保护作用。具体地说，它们显著减少了细胞凋亡和活性氧的产生，并改善了体外线粒体的新陈代谢。SHLP2和SHLP3也促进3T3-L1前脂肪细胞分化。全身性高胰岛素-正常血糖钳夹研究表明，脑内注入SHLP2可增加葡萄糖摄取并抑制肝脏葡萄糖的产生，这表明它在外周和中枢都起着胰岛素增敏剂的作用。与HN相似，循环SHLP2水平随年龄增长而降低。这些结果表明，线粒体通过合成线粒体肽在新陈代谢和生存中起着关键作用，并为线粒体生物学与衰老和人类生物学的相关研究提供了新的视角。
Mitochondria are key players in aging and in the pathogenesis of age-related diseases. Recent mitochondrial transcriptome analyses revealed the existence of multiple small mRNAs transcribed from mitochondrial DNA (mtDNA). Humanin (HN), a peptide encoded in the mtDNA 16S ribosomal RNA region, is a neuroprotective factor. An in silico search revealed six additional peptides in the same region of mtDNA as humanin; we named these peptides small humanin-like peptides (SHLPs). We identified the functional roles for these peptides and the potential mechanisms of action. The SHLPs differed in their ability to regulate cell viability in vitro. We focused on SHLP2 and SHLP3 because they shared similar protective effects with HN. Specifically, they significantly reduced apoptosis and the generation of reactive oxygen species, and improved mitochondrial metabolism in vitro. SHLP2 and SHLP3 also enhanced 3T3-L1 pre-adipocyte differentiation. Systemic hyperinsulinemic-euglycemic clamp studies showed that intracerebrally infused SHLP2 increased glucose uptake and suppressed hepatic glucose production, suggesting that it functions as an insulin sensitizer both peripherally and centrally. Similar to HN, the levels of circulating SHLP2 were found to decrease with age. These results suggest that mitochondria play critical roles in metabolism and survival through the synthesis of mitochondrial peptides, and provide new insights into mitochondrial biology with relevance to aging and human biology.