# MCL-1 is a critical regulator of mitochondrial dynamics and function in myocytes

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $458,985

## Abstract

Project Summary
While mitochondrial dysfunction is evident in the failing heart, its precise role in disease progression is unclear
and the mechanism(s) of its origin is not well understood. Mitochondria play a key role in many cellular processes,
including oxidative phosphorylation, metabolite synthesis and calcium storage. They are also important
regulators of cell death and monitor changes in the intracellular environment such as presence of reactive oxygen
species and DNA damage. The BCL-2 proteins play a key role in regulating mitochondrial membrane
permeabilization and apoptosis. We recently discovered that the anti-apoptotic BCL-2 protein MCL-1 is critical
for normal mitochondrial function and cardiac homeostasis. Loss of MCL-1 in cardiac myocytes leads to rapid
mitochondrial dysfunction, development of heart failure, and early mortality. Surprisingly, MCL-1 deficient
myocytes display signs of necrosis rather than apoptosis as would be expected, suggesting that besides its anti-
apoptotic role, MCL-1 has an essential but yet unidentified role in maintaining mitochondrial function in cardiac
myocytes. We have also found that MCL-1 exists both in the outer mitochondrial membrane (MCL-1OM) and in
the mitochondrial matrix (MCL-1Matrix) in the heart. While a study has implicated MCL-1OM in regulating apoptosis,
the function of MCL-1Matrix is still unknown. Based on our preliminary data, we propose to study the hypothesis
that MCL-1 has a dual role in maintaining cardiac mitochondrial function and health that is dependent on its
mitochondrial location: MCL-1OM facilitates mitochondrial fission and mitophagy of aberrant mitochondria to
prevent activation of unnecessary apoptosis, whereas MCL-1Matrix promotes mitochondrial fusion to preserve
bioenergetic capacity and protect against autophagosomal degradation during nutrient limiting conditions. This
hypothesis will be tested with three specific aims. In Specific Aim 1, we will characterize the role of MCL-1Matrix
in regulating mitochondrial fusion, function, turnover and survival. In Specific Aim 2, we will delineate the role of
MCL-1OM in regulating mitochondrial fission and turnover. We will determine if MCL-1OM interacts with Drp1 to
promote asymmetrical fission and removal of damaged mitochondria and whether this is part of its pro-survival
function. Finally, in Specific Aim #3, we will investigate whether MCL-1OM also functions as a receptor for LC3 to
drive selective degradation of mitochondrial by autophagosomes. We will utilize both isolated cardiac myocytes
and genetically modified mouse models combined with proteomics, cell and molecular biology to uncover the bi-
functional roles of MCL-1OM and MCL-1Matrix in myocytes under baseline conditions and in response to challenge
(fasting and myocardial infarction). These studies will provide important new insights into the relationship
between mitochondrial dynamics, turnover and survival in the heart. A better understanding of how mitochondr...

## Key facts

- **NIH application ID:** 9847996
- **Project number:** 5R01HL132300-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Asa B. Gustafsson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $458,985
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847996

## Citation

> US National Institutes of Health, RePORTER application 9847996, MCL-1 is a critical regulator of mitochondrial dynamics and function in myocytes (5R01HL132300-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9847996. Licensed CC0.

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