# Myocardial Infarction in the Aging Heart: Ischemia-Damaged Mitochondria, Reticulum Stress and the Transition to Heart Failure

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2020 · —

## Abstract

Cardiovascular disease increases markedly with advancing age in our Veteran population. In aging,
myocardial injury is increased during ischemia (ISC)-reperfusion (REP) and leads to heart failure.
Mitochondrial-driven injury during ISC-REP in aged hearts is mediated by the electron transport chain (ETC)
due to increased production of reactive oxygen species (ROS) and damage to the mitochondrial phospholipid
cardiolipin (CL). Most therapeutic strategies that effectively decrease cardiac injury in younger hearts fail in
aged hearts. In contrast, we found that a transient, reversible inhibition of ETC complex I during early REP
decreased injury in the aged heart. The key mechanism and target of protection at the cellular level that
mediates ETC-driven protection remains a critical unanswered question.
 In addition to mitochondria (MITO) damage, endoplasmic reticulum (ER) stress contributes to cardiac
injury. MITO and ER are juxtaposed through shared structures of mitochondria-associated membranes
(MAM). MAM contribute a critical role in calcium regulation and lipid metabolism between MITO and ER.
Disruption of MAM integrity likely mediates pathologic “cross talk” between ER and MITO and increases
cardiac injury. We found that CL exists in MAM and the ER with a composition distinct from MITO. Our
previous work showed that CL content in MITO is decreased and exhibits an increase in oxidized CL content
following ISC-REP in the aged heart. ER is a key site for the remodeling/repair of damaged CL. We
hypothesize that CL is a key mediator of the “cross talk” between MITO and ER via the MAM, and that
trafficking of damaged CL to ER via the MAM is a mediator of MAM disruption in the aged heart during
ISC-REP.
 Age-induced ETC defects increase ROS production. MITO ROS can damage MAM and activate ER
stress responses. We found that aging augments cardiac ER stress. MAM are uniquely positioned to sustain
damage from both MITO and ER. The increased ROS from aged heart MITO may damage CL in the MAM
and activate ER stress. We will evaluate the role of primary MITO dysfunction at baseline and then following
ISC and early REP to MAM damage and CL modification in Aim 1. The role of ETC inhibition to protect MAM
during ISC-REP is studied (Aim 1).
 The response of MAM and ER to ISC-REP in the aged heart is unknown (Aim 2). Acute, transient
complex I blockade with a reversible inhibitor decreases injury in aged hearts. We found that metformin
inhibits complex I in a dose-dependent manner, especially in ISC-damaged heart MITO. Next, we showed that
metformin treatment only at REP in doses that inhibit complex I decreases infarct size in vivo following 24 hrs.
REP. We hypothesize that modulation of complex I at REP in aged hearts will attenuate damage to the MAM
with a subsequent decrease in ER stress that, in turn, minimizes the generation of dysfunctional MITO and
cardiac injury. The partial inhibition of complex I is studied as a new upstream therapeutic intervention to...

## Key facts

- **NIH application ID:** 9814675
- **Project number:** 5I01BX001355-08
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Edward J Lesnefsky
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9814675

## Citation

> US National Institutes of Health, RePORTER application 9814675, Myocardial Infarction in the Aging Heart: Ischemia-Damaged Mitochondria, Reticulum Stress and the Transition to Heart Failure (5I01BX001355-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9814675. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*