# Molecular Determinants of Mitochondrial Instability and Arrhythmias

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $502,067

## Abstract

Sudden Cardiac Death (SCD) occurs in more than half a million people every year and arrhythmias, resulting in
hemodynamic insufficiency followed by death, account for the majority of SCD cases. Arrhythmias secondary to
scar formation are well understood, but mechanisms by which acute ischemia/reperfusion (I/R) injury promotes
ventricular tachycardia and fibrillation (VT/VF) are more complex. I/R-related arrhythmias depend on dynamic
properties of the tissue, including Ca2+-mediated triggers, functional conduction block, decreased gap junctional
conductance, heterogeneous shortening of the action potential (AP) and dispersion of refractoriness. These
complex electrophysiological (EP) changes are caused by limitations in ATP supply, changes in reactive oxygen
species (ROS), accumulation of detrimental intracellular (Ca2+, Na+, acid) and extracellular (K+, lactate)
constituents, all of which can be traced to a common origin, namely impaired mitochondrial function. Our group
was the first to recognize the importance of heterogeneous mitochondrial instability, including sustained
depolarization or oscillation of the mitochondrial inner membrane potential (∆Ψm), across clusters of
myocytes or regions within the heart, in setting the stage for VT/VF. However, the mechanisms behind
mitochondrial instability during reperfusion are unclear and how they contribute to arrhythmias is not well
understood. While inhibition of the mitochondrial permeability transition pore (mPTP) decreases infarct size,
cyclosporine A-mediated inhibition of mPTP has little or no effect on arrhythmia incidence after ischemia,
suggesting that the early dysfunction and late injury mechanisms may be distinct. In contrast, we found that
mitochondrial benzodiazepine receptor (mBzR) ligands are very effective at restoring the action potential and
suppressing arrhythmias induced by I/R, in parallel with their ability to prevent or reverse mitochondrial
depolarization. Indeed, our exciting preliminary data suggests that mBzR, rather than mPTP, is more important
in terms of ∆Ψm and electrical stability during the early reperfusion phase. Here, we will use innovative
approaches to image the dynamics of ∆Ψm, Vm, matrix Ca and ROS during I/R at the cellular and whole
2+
heart scales, combined with powerful genetic models to selectively knockout the key proteins involved
in modulating mPTP (cyclophilin D; PPIF), mitochondrial Ca2+ (the mitochondrial Ca2+uniporter; MCU),
and the mBzR (translocator protein; TSPO), to define the causal mechanisms underlying mitochondrial
instability and arrhythmias on reperfusion. This project will move the field from conclusions based on
pharmacological inference to molecular understanding, allowing us to focus our efforts on the correct
mitochondrial targets to pursue to prevent I/R-induced arrhythmias with the goal of decreasing the burden of
SCD.

## Key facts

- **NIH application ID:** 9857647
- **Project number:** 5R01HL137259-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** FADI GABRIEL AKAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $502,067
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857647

## Citation

> US National Institutes of Health, RePORTER application 9857647, Molecular Determinants of Mitochondrial Instability and Arrhythmias (5R01HL137259-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857647. Licensed CC0.

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