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

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2024 · —

## Abstract

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 c...

## Key facts

- **NIH application ID:** 10726565
- **Project number:** 5I01BX001355-11
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Edward J Lesnefsky
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-04-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726565

## Citation

> US National Institutes of Health, RePORTER application 10726565, Mitochondrial Dysfunction in the Aged Heart:  Role of Endoplasmic Reticulum Stress (5I01BX001355-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10726565. Licensed CC0.

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