Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure

Area of Science:

• Cardiology
• Mitochondrial Biology
• Biochemistry

Background:

• Mitochondrial respiratory dysfunction is implicated in heart failure pathogenesis.
• The precise mechanisms linking mitochondrial dysfunction to heart disease remain unclear.

Purpose of the Study:

• To investigate the role of mitochondrial complex I deficiency in cardiac function and heart failure.
• To elucidate the molecular mechanisms underlying mitochondrial dysfunction-induced heart problems.

Main Methods:

• Generated cardiac-specific Ndufs4 knockout (cKO) mice to model complex I deficiency.
• Assessed cardiac function in vivo and in isolated perfused hearts.
• Analyzed mitochondrial NAD+/NADH ratio, Sirt3 activity, protein acetylation, and mitochondrial permeability transition pore (mPTP) sensitivity.

Main Results:

• cKO mice showed >40% decrease in complex I respiration but maintained normal cardiac function and energy levels initially.
• Pressure overload or pregnancy induced accelerated heart failure in cKO mice.
• Complex I deficiency decreased NAD+/NADH ratio, inhibited Sirt3, increased protein acetylation, and sensitized mPTP.
• NAD+ precursor supplementation partially restored NAD+/NADH ratio, protein acetylation, and mPTP sensitivity.

Conclusions:

• Cardiac complex I deficiency sensitizes the heart to stress-induced failure through altered NAD+/NADH ratio, Sirt3 activity, and mPTP regulation.
• NAD+ precursor supplementation may represent a therapeutic strategy for mitochondrial dysfunction-related heart conditions.