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

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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.