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CLIC4 localizes to mitochondrial-associated membranes and mediates cardioprotection

Devasena Ponnalagu1,2, Shanna Hamilton1,2, Shridhar Sanghvi1,2

  • 1Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA.

Science Advances
|October 21, 2022
PubMed

Insights

Chloride intracellular channel protein 4 (CLIC4) in mitochondrial-associated membranes (MAMs) protects the heart from ischemia-reperfusion injury. Loss of CLIC4 worsens heart attack size and cardiac function, highlighting its therapeutic potential.

Area of Science:

  • Cardiovascular Biology
  • Cellular Biology
  • Mitochondrial Dynamics

Background:

  • Mitochondrial-associated membranes (MAMs) regulate cellular functions and impact myocardial ischemia-reperfusion (IR) injury.
  • Identifying MAM targets is crucial for developing effective IR injury therapeutics.

Purpose of the Study:

  • To investigate the role of chloride intracellular channel protein 4 (CLIC4) in MAMs during myocardial IR injury.
  • To elucidate CLIC4's function in maintaining ER and mitochondrial calcium homeostasis.

Main Methods:

  • Localization of CLIC4 in cardiomyocyte MAMs.
  • Assessment of myocardial infarction and cardiac function in a murine model of IR injury.
  • Evaluation of cardiomyocyte apoptosis and mitochondrial function under hypoxia-reoxygenation.

Main Results:

  • CLIC4 was identified in cardiomyocyte MAMs, modulating calcium homeostasis.
  • Loss of CLIC4 exacerbated myocardial infarction and reduced cardiac function post-IR.
  • CLIC4-deficient cardiomyocytes exhibited increased apoptosis and mitochondrial dysfunction following hypoxia-reoxygenation.

Conclusions:

  • MAM-localized CLIC4 is a key mediator in the cellular response to IR injury.
  • CLIC4 plays a protective role against cardiac IR injury by maintaining calcium homeostasis and mitochondrial function.
  • CLIC4 represents a potential therapeutic target for myocardial IR injury and other related pathophysiological processes.

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