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

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Principal Investigator: Edward J Lesnefsky
Organization: VA VETERANS ADMINISTRATION HOSPITAL
Fiscal Year: 2024
Funding agency: Veterans Affairs

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.

Terms: <(hydroxymethylglutaryl-CoA reductase (NADPH)) kinase><21+ years old><5'-AMP-activated protein kinase><AMP-activated kinase><AMP-activated protein kinase><AMPK enzyme><ATP-protein phosphotransferase><Abscission><Acceleration><Active Oxygen><Acute><Adult><Adult Human><Age><Aging><Back><Blood flow><Ca2+-Activated Protease><Calcium><Calcium-Activated Neutral Protease><Calcium-Activated Neutral Proteinase><Calcium-Activated Protease><Calcium-Dependent Neutral Protease><Calcium-Dependent Neutral Proteinase><Calpain><Cardiac Diseases><Cardiac Disorders><Cardiac artery><Cardiac infarction><Cardiovascular Diseases><Cell Communication and Signaling><Cell Death><Cell Signaling><Cellular Expansion><Cellular Growth><Cellular Stress><Cellular Stress Response><Chronic><Complex><Coronary Arteriosclerosis><Coronary Artery Disease><Coronary Artery Disorder><Coronary Atherosclerosis><Coronary artery><Cytosol><Defect><Desminase><Dimethylbiguanidine><Dimethylguanylguanidine><Disparities><Disparity><Dorsum><Down-Regulation><Dysfunction><ER stress><Elderly><Electron Transport><Endoplasmic Reticulum><Ergastoplasm><Esteroproteases><Excision><Extirpation><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Functional disorder><Genes><HMG CoA reductase (NADPH) kinase><HMG CoA reductase kinase><HMG coenzyme A reductase (NADPH) kinase><Heart><Heart Diseases><Heart Injuries><Heart artery><Heart failure><Impairment><Incidence><Injury><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ischemia><Kinase Family Gene><Lead><Link><Mechanistic Target of Rapamycin><Mediating><Membrane><Metabolic><Metabolic stress><Metformin><Mitochondria><Myocardial Infarct><Myocardial Infarction><Myocardium><N,N-dimethyl-imidodicarbonimidic diamide><Oxidative Phosphorylation><Oxidative Phosphorylation Pathway><Oxygen Radicals><Papain-Like Cysteine Protease><Patients><Pb element><Peptidases><Peptide Hydrolases><Physiopathology><Predisposition><Pro-Oxidants><Production><Protease Gene><Proteases><Protein Biosynthesis><Protein Complex Subunit><Protein Kinase><Proteinases><Proteins><Proteolytic Enzymes><RAFT1><Reactive Oxygen Species><Removal><Reperfusion Therapy><Research><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Risk><Role><Scheme><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Structure><Surgical Removal><Susceptibility><Therapeutic><Up-Regulation><Upregulation><Veterans><Work><aberrant aging><abnormal aging><adulthood><advanced age><age associated><age correlated><age dependent><age linked><age related><age specific><aged><aged mice><aged mouse><ages><aging associated mechanism><aging mechanism><aging pathway><aging related mechanism><aging reversal><atherosclerotic coronary disease><attenuation><biological adaptation to stress><biological mechanism of age><biological pathways of age><biological signal transduction><cardiac damage><cardiac failure><cardiac infarct><cardiac injury><cardiac muscle><cardiovascular disorder><cell growth><cell stress><clinical relevance><clinically relevant><coronary arterial disease><coronary attack><coronary infarct><coronary infarction><dysfunctional age related change><dysfunctional aging><elderly mice><elderly patient><electron transfer><endoplasmic reticulum stress><feeding><geriatric><glycogen synthase a kinase><heart attack><heart cell><heart damage><heart disorder><heart infarct><heart infarction><heart muscle><heavy metal Pb><heavy metal lead><hydroxyalkyl protein kinase><hydroxymethylglutaryl-CoA-reductase kinase><impaired aging><improved><injuries><injury to the myocardium><insight><insulin signaling><interventional strategy><ischemia injury><ischemic injury><mTOR><maladaptive aging><mammalian target of rapamycin><membrane structure><military veteran><mitochondrial><mitochondrial dysfunction><myocardial injury><necrocytosis><novel><old mice><older patient><pathological age related changes><pathological aging><pathophysiology><phosphorylase b kinase kinase><pre-clinical study><preclinical study><programs><protein synthesis><reaction; crisis><reperfusion><resection><restoration><reverse aging><reverse aging effects><reversible aging><senior citizen><social role><stress response><stress; reaction><translational opportunities><translational potential><veteran population>