Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
Tom70-based transcriptional regulation of mitochondrial biogenesis and aging.
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作者：
Liu Q;Chang CE;Wooldredge AC;Fong B;Kennedy BK;Zhou C
线粒体生物发生有两个主要步骤：核基因组编码的线粒体蛋白的转录激活和在胞质溶胶中合成的新生线粒体蛋白的输入。这些新生的线粒体蛋白是聚集倾向，并能引起胞质蛋白质稳态应激。转录因子依赖的转录调控和TOM-TIM复合物依赖的新生线粒体蛋白的输入已被广泛研究。然而，关于线粒体生物发生的这两个步骤如何相互协调以避免这些易于聚集的新生线粒体蛋白质的胞质积累知之甚少。在这里，我们表明，在芽殖酵母，Tom 70，一个保守的受体的TOM复合物，月光调节线粒体蛋白的转录活性。Tom 70的转录调控作用在果蝇中是保守的。Tom 70在线粒体蛋白的转录/生物发生和输入中的双重作用允许细胞在不损害胞质蛋白质稳定的情况下实现线粒体生物发生。Tom 70的生物合成减少和降解增加引起的与年龄相关的Tom 70减少与线粒体膜电位、mtDNA和线粒体蛋白的损失有关。虽然Tom 70的丢失加速了衰老和与年龄相关的线粒体缺陷，但过表达TOM 70延迟了这些线粒体功能障碍并延长了复制寿命。我们的研究结果揭示了Tom 70在线粒体生物发生和衰老中的意想不到的作用。
Mitochondrial biogenesis has two major steps: the transcriptional activation of nuclear genome-encoded mitochondrial proteins and the import of nascent mitochondrial proteins that are synthesized in the cytosol. These nascent mitochondrial proteins are aggregation-prone and can cause cytosolic proteostasis stress. The transcription factor-dependent transcriptional regulations and the TOM-TIM complex-dependent import of nascent mitochondrial proteins have been extensively studied. Yet, little is known regarding how these two steps of mitochondrial biogenesis coordinate with each other to avoid the cytosolic accumulation of these aggregation-prone nascent mitochondrial proteins. Here, we show that in budding yeast, Tom70, a conserved receptor of the TOM complex, moonlights to regulate the transcriptional activity of mitochondrial proteins. Tom70’s transcription regulatory role is conserved in Drosophila. The dual roles of Tom70 in both transcription/biogenesis and import of mitochondrial proteins allow the cells to accomplish mitochondrial biogenesis without compromising cytosolic proteostasis. The age-related reduction of Tom70, caused by reduced biogenesis and increased degradation of Tom70, is associated with the loss of mitochondrial membrane potential, mtDNA, and mitochondrial proteins. While loss of Tom70 accelerates aging and age-related mitochondrial defects, overexpressing TOM70 delays these mitochondrial dysfunctions and extends the replicative lifespan. Our results reveal unexpected roles of Tom70 in mitochondrial biogenesis and aging.