Mitochondrial uncoupling downregulates calsequestrin expression and reduces SR Ca2+ stores in cardiomyocytes

Area of Science:

• Cardiovascular Biology
• Mitochondrial Physiology
• Cellular Signaling

Background:

• Mitochondrial cardiomyopathy involves abnormal cardiomyocyte calcium (Ca2+) signaling, partly due to reduced calsequestrin (CASQ2) expression.
• Calsequestrin (CASQ2) is a key sarcoplasmic reticulum (SR) calcium buffer in cardiomyocytes.

Purpose of the Study:

• To investigate if impaired mitochondrial function directly causes CASQ2 downregulation.
• To elucidate the role of reactive oxygen species (ROS) in this process.

Main Methods:

• Cultured neonatal rat cardiomyocytes were subjected to mitochondrial stress using FCCP (carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone).
• Calcium (Ca2+) transients and ROS were measured using confocal microscopy.
• The effects of caspase inhibitors and ROS scavengers (NAC) were assessed.

Main Results:

• Mitochondrial stress induced concentration-dependent CASQ2 downregulation and altered cardiomyocyte Ca2+ signals.
• SR Ca2+ content and Ca2+ spark properties were reduced.
• N-acetylcysteine (NAC) attenuated CASQ2 downregulation and restored Ca2+ signaling by reducing ROS.

Conclusions:

• Mitochondrial uncoupling triggers rapid transcriptional changes in CASQ2, impairing Ca2+ signaling.
• ROS are key mediators of this downregulation.
• These findings suggest a mechanism relevant to cardiac pathologies and aging.