TECRL deficiency results in aberrant mitochondrial function in cardiomyocytes

Area of Science:

• Cardiology
• Molecular Biology
• Cell Biology

Background:

• Sudden cardiac death (SCD) from ventricular arrhythmias is a major cause of cardiovascular mortality.
• Mutations in TECRL, an endoplasmic reticulum protein, have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT) and SCD.

Purpose of the Study:

• To investigate the role of TECRL in cardiac function and mitochondrial respiration.
• To elucidate the molecular mechanisms by which TECRL regulates cardiomyocyte function and survival.

Main Methods:

• Utilized loss- and gain-of-function approaches in murine and human cardiomyocytes.
• Analyzed cardiac function using ejection fraction and fractional shortening in Tecrl knockout mice.
• Assessed mitochondrial respiration, ATP production, and protein expression (MFN2, p-AKT, NRF2, AIF, Cyc).

Main Results:

• Tecrl knockout mice exhibited aggravated cardiac dysfunction and impaired mitochondrial respiration.
• TECRL deficiency reduced ATP production, increased fatty acid synthase and reactive oxygen species, and decreased MFN2, p-AKT, and NRF2.
• TECRL overexpression enhanced mitochondrial respiration via PI3K/AKT signaling and MFN2.
• Knockdown of TECRL led to the release of apoptosis-inducing factor and cytochrome C from mitochondria.

Conclusions:

• TECRL plays a critical role in maintaining cardiac function and mitochondrial health.
• TECRL regulates mitochondrial function through PI3K/AKT signaling and MFN2.
• TECRL represents a potential therapeutic target for CPVT and related conditions.