Mitochondrial biogenesis, genetics and cell loss in mammalian aging

项目总结/摘要 线粒体生物发生是许多衰老干预的目标。虽然诱导线粒体 生物发生通常被认为是有益的，我们的数据表明，激活线粒体生物发生， 老年驱动线粒体DNA（mtDNA）缺失突变的细胞内积累， 肌肉纤维减少18%，电子传递链（ETC）缺陷的肌肉纤维增加1,200% 片段这些作用具有拮抗多效性;在给药的幼龄大鼠中未观察到。基于 根据我们的数据，老年人线粒体生物合成的上调可能会导致骨骼肌 损害这些研究将阐明线粒体生物发生在mtDNA缺失突变中的作用 积累，并评估刺激线粒体生物发生的化合物的老年特异性作用 在骨骼肌中。 项目成果： ·指定诱导线粒体生物合成增加mtDNA的细胞途径和年龄 缺失突变频率、ETC缺陷和纤维丢失。 ·通过指定事件和时间的顺序推断纤维损失中线粒体生物发生的因果关系 线粒体生物发生、线粒体DNA缺失突变积累和细胞死亡之间所必需的。 ·确定是否有其他AMPK或过氧化物酶体增殖物激活受体激动剂，其靶向 线粒体生物发生，也诱导缺失突变积累和细胞死亡时，启动在老年人 年龄 ·下调老年大鼠的线粒体生物合成，以防止ETC缺乏和纤维丢失。 通过了解老年诱导线粒体生物合成的机制和影响，我们将 指定减轻拮抗作用的目标和治疗策略。

PROJECT SUMMARY/ABSTRACT Mitochondrial biogenesis is a target of many aging interventions. While the induction of mitochondrial biogenesis is generally thought to be beneficial, our data indicate that activating mitochondrial biogenesis at old age drives the intracellular accumulation of mitochondrial DNA (mtDNA) deletion mutations and results in an 18% loss of muscle fibers and a 1,200% increase in electron transport chain (ETC) deficient muscle fiber segments. These effects were antagonistically pleiotropic; they were not observed in treated young rats. Based on our data, up-regulation of mitochondrial biogenesis in aged humans may cause significant skeletal muscle damage. These studies will clarify the role of mitochondrial biogenesis in mtDNA deletion mutation accumulation and evaluate the old-age specific effects of compounds that stimulate mitochondrial biogenesis in skeletal muscle. Project outcomes: · Specify the cellular pathways and ages at which inducing mitochondrial biogenesis increases mtDNA deletion mutation frequency, ETC deficiencies and fiber loss. · Infer the causality of mitochondrial biogenesis in fiber loss by specifying the order of events and time required between mitochondrial biogenesis, mtDNA deletion mutation accumulation and cell death. · Determine whether other AMPK or peroxisome proliferator-activated receptor agonists, which target mitochondrial biogenesis, also induce deletion mutation accumulation and cell death when initiated at old ages. · Downregulate mitochondrial biogenesis in old rats to prevent ETC deficiencies and fiber loss. By understanding the mechanisms and impacts of inducing mitochondrial biogenesis at old ages, we will specify targets and treatment strategies that mitigate the antagonistic effects.