Aging and decline in mitochondrial function are closely linked. Key signs of mitochondrial dysfunction include increased generation of reactive oxygen species, fewer ATP molecules produced per O2 consumed, and increased apoptosis. The reduction in ATP translates to lower energy for cellular maintenance processes including mitobiogenesis and turnover. We recently reported the identification of a functional Mitochondrial Angiotensin System (MAS), and found that aging impacts the ratio of key angiotensin type 1 and type 2 receptors in mitochondria (AT1R and AT2R), that AT1R blocking agents may partially reverse these changes and improve mitochondrial function. Importantly, AT1R-/- mice have an enhanced life span by 25%, in part through an increase in mitochondrial numbers. The effects of aging on the expression of mitochondrial (mt) AT1R and mtAT2R and their contribution to age-related changes in mitochondrial dysfunction has not been previously studied. New preliminary evidence suggests that AT1R blockade in old mice may restore the age- related decline in mitochondrial energy production and improve mitophagy efficiency via alterations in p53- inducible protein (MIEAP) expression. We hypothesize that an age-related increase in mtAT1R/AT2R ratio mediates declines in mitochondrial energy metabolism via increased reactive oxygen species (ROS) production and impaired elimination of damaged mitochondria. In order to test this hypothesis we propose a comprehensive study of mtAT1R and mtAT2R, in control and losartan (AT1R blocker) treated, young and aged (38-month old) C57BL/6, AT1-/- and AT2-/- mice. Will use age related cardiac muscle bioenergetics failure as a model to study the impact of changes in mtAT1R and mtAT2R following proposed specific aims: 1. To identify age-related changes in peripheral angiotensin system (PAS) and MAS and their contribution to altered reactive nitrogen/oxygen species ROS/RNS generation, using Q-PCR, western blot, confocal and electron microscopy. Generation of ROS/RNS will be quantified in isolated cardiomyocytes and mitochondria from all our animal groups using specific fluorescent probes. 2. To specify the contribution of age-related changes in PAS and MAS to bioenergetic dysfunction by magnetic resonance spectroscopy and imaging in the cardiac tissue of living animals at baseline and after four weeks of placebo or losartan treatment. MAS contributions to the changes in bioenergetics will studied in isolated cardiac mitochondria from all animal groups. 3. To investigate the role of the PAS and MAS on mitochondrial biogenesis, repair, and elimination by utilizing a cardiac cell line (H9C2) instrumented with a P53 activity reporter to measure the effects of over-expressing AT1R and/or AT2R on MIEAP, oxidative stress, mtDNA damage and mitophagy. Similar outcomes will also be compared between control and LOS treated, young and aged (38-month old) C57BL/6, AT1-/- and AT2-/- mice.
This study is designed to evaluate specific factors in mitochondria that may play a role in late life weakness and increased vulnerability to disease states. Angiotensin receptors 1 and 2 (AT1R and AT2R) are found on the surface and on the inside the mitochondria of virtually all human cells. This study will evaluate how the relationship among these mitochondrial receptors in cardiac cells change with aging, and how these changes might trigger mitochondrial dysfunction, declines in energy production, and cellular decline in older organisms.
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