MICU3 Regulates Mitochondrial Calcium and Cardiac Hypertrophy.

Area of Science:

• Cardiovascular Biology
• Mitochondrial Physiology
• Molecular Cardiology

Background:

• Mitochondrial calcium (Ca²⁺) uptake is crucial and mediated by the mitochondrial Ca²⁺ uniporter complex.
• This complex is regulated by MICU (mitochondrial Ca²⁺ uptake) proteins, including MICU1, MICU2, and MICU3.
• The specific role of MICU3 in cardiac physiology remains largely uncharacterized.

Purpose of the Study:

• To investigate the function of MICU3 in regulating mitochondrial calcium uptake in the heart.
• To determine the impact of altered MICU3 expression on cardiac function and mitochondrial Ca²⁺ handling.
• To assess MICU3 expression in failing human hearts.

Main Methods:

• Generated MICU3 knockout mice using CRISPR-Cas9 and MICU3 overexpressing mice via AAV9.
• Assessed mitochondrial Ca²⁺ ([Ca²⁺]_m) in ex vivo hearts using optical methods after adrenergic stimulation.
• Evaluated in vivo cardiac function using echocardiography and analyzed mitochondrial complex composition.

Main Results:

• MICU3 knockout hearts showed reduced [Ca²⁺]_m increase, while MICU3 overexpression enhanced it.
• Cardiac function was unchanged in MICU3 knockout mice but impaired (reduced ejection fraction) in MICU3 overexpressing mice.
• MICU3 overexpression led to cardiac hypertrophy, and MICU3 expression was decreased in failing human hearts.

Conclusions:

• MICU3 expression levels directly modulate cardiac mitochondrial Ca²⁺ uptake.
• Overexpression of MICU3 induces cardiac hypertrophy, highlighting its potential as a therapeutic target.
• MICU3 is implicated in cardiac pathophysiology and warrants further investigation.