Mitochondrial Dysfunction in the Aged Heart: Role of Endoplasmic Reticulum Stress

老年心脏缺血再灌注期心肌损伤加重 加速向梗死后心力衰竭的转变。大多数治疗策略 有效减少年轻心脏的心脏损伤，老年心脏衰竭。老化原因 线粒体功能障碍，增加了因缺血和再灌流造成的心脏损伤。老龄化 损伤电子传递链，氧化磷酸化减少，增加 产生活性氧物种。因此，迫切需要了解这些机制。 在这种情况下，年龄引起的代谢缺陷会导致伤害增加。我们发现内质网 随着年龄的增长，网状结构(ER)应激增加。我们证明了用药物治疗衰老小鼠 减少内质网应激的干预显著改善老年心脏的线粒体功能。 随着基线线粒体功能的改善，随后的心脏损伤 缺血再灌注期明显减少。 络合物I是电子传递链中的限速步骤。我们发现了关键蛋白质 随着年龄的增长，复合体I的亚基减少。Mito定位的蛋白酶calain的活性是 随着年龄的增长而增加。我们假设内质网应激激活线粒体定位 导致复合体I亚单位耗竭和复合体I功能障碍的钙蛋白 导致年龄引起的线粒体功能障碍。目的1研究内质网的作用机制 应激通过激活线粒体钙蛋白介导复合体i的损伤。我们正在进行的工作 显示慢性二甲双胍治疗通过改善线粒体减少内质网应激 在衰老的心脏中起作用。AMPK与雷帕霉素的作用靶点 (MTOR)是对新陈代谢和细胞应激做出反应的关键效应因子。MTORC1信号转导 调节蛋白质合成，并与内质网应激有关。MTORC2调节细胞生长和 胰岛素信号。我们发现了老年心脏中mTORC1活性增加的证据 二甲双胍治疗后mTORC1表达下调。我们假设二甲双胍 通过AMPK介导的mTORC1下调来减轻内质网应激。 由此产生的功能障碍的线粒体需要通过有丝分裂来移除，这是 在老年心脏中降低。AMPK和mTOR调节有丝分裂吞噬。在最初的工作中，我们发现 在老年心脏中，二甲双胍治疗通过AMPK信号激活有丝分裂。 因此，二甲双胍治疗有可能减少内质网应激介导的直接损伤 通过钙蛋白酶激活线粒体并促进功能障碍的线粒体的清除 老旧的心。目的2研究二甲双胍下调内质网应激的机制 通过调制mTORC1和mTORC2信号影响内质网应激的治疗 反应基因程序与潜在的增强有丝分裂吞噬。年龄诱导型 线粒体功能障碍增加老年心脏对损伤的易感性 随后的缺血和再灌流。我们假设线粒体的恢复 长期服用二甲双胍可减少老年心脏的损伤。 老年心脏线粒体功能恢复对减轻心肌损伤的作用 随后的缺血和再灌注在目标3中进行了研究。这一建议促进了我们的 衰老过程中内质网应激介导的线粒体功能障碍机制的研究 并提供指导，以开发临床相关的方法来减少 改善老年心脏线粒体功能造成的心脏损伤。

Myocardial injury is increased during ischemia and reperfusion in the aged heart and accelerates the transition to post-infarction heart failure. Most therapeutic strategies that effectively decrease cardiac injury in younger hearts fail in aged hearts. Aging causes dysfunctional mitochondria that increase cardiac injury from ischemia and reperfusion. Aging impairs the electron transport chain with decreased oxidative phosphorylation and increased production of reactive oxygen species. Thus, it is a critical need to understand the mechanisms by which age-induced metabolic defects lead to increased injury. We found that endoplasmic reticulum (ER) stress increases during aging. We showed that treatment of aged mice with intervention to decrease ER stress markedly improved mitochondrial function in aged hearts. Following the improvement in baseline mitochondrial function, cardiac injury from a subsequent episode of ischemia and reperfusion was markedly reduced. Complex I is a rate limiting step in the electron transport chain. We found that key protein subunits of complex I are decreased by aging. Activity of the MITO localized protease calpain is increased during aging. We hypothesize that ER stress activates mitochondria-localized calpain causing depletion of subunits of complex I and impairment of complex I function leading to age-induced mitochondrial dysfunction. Aim 1 studies the mechanism of the ER stress mediated injury to complex I via activation of mitochondrial calpain. Our ongoing work showed that chronic metformin treatment reduced ER stress with improved mitochondrial function in aged hearts. AMP protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) are key effectors that respond to metabolic and cell stress. mTORC1 signaling regulates protein synthesis and is linked to ER stress. mTORC2 regulates cell growth and insulin signaling. We found evidence of increased mTORC1 activation in the aged heart with downregulation of mTORC1 following metformin therapy. We hypothesize that metformin decreases ER stress via AMPK-mediated downregulation of mTORC1. The resulting dysfunctional mitochondria need be removed by mitophagy, which is decreased in the aged heart. AMPK and mTOR modulate mitophagy. In initial work, we found that metformin treatment in the aged heart activates mitophagy through AMPK signaling. Metformin treatment thus has the potential to both decrease ER stress mediated direct injury to mitochondria via calpain activation and to facilitate the removal of dysfunctional mitochondria in aged hearts. Aim 2 studies the mechanisms of the downregulation of ER stress by metformin treatment via modulation of mTORC1 and mTORC2 signaling that impacts the ER stress response gene program with the potential enhancement of mitophagy. Age-induced mitochondrial dysfunction increases the susceptibility of the aged heart to injury from subsequent ischemia and reperfusion. We hypothesize that restoration of mitochondrial function with chronic metformin feeding will decrease cardiac injury in the aged hearts. The contribution of restored mitochondrial function in the aged heart to decrease injury from subsequent ischemia and reperfusion is studied in Aim 3. This proposal advances our understanding of the mechanisms of ER stress-mediated mitochondrial dysfunction during aging in the heart and provides guidance to develop clinically relevant approaches to decrease cardiac injury by improving mitochondrial function in aged hearts.