Heart specific knockout of Ndufs4 ameliorates ischemia reperfusion injury

Area of Science:

• Cardiovascular Biology
• Mitochondrial Physiology
• Oxidative Stress

Background:

• Ischemic heart disease (IHD) is a major cause of death globally.
• Reperfusion therapy for IHD can paradoxically cause ischemia-reperfusion (I/R) injury.
• Oxidative stress and cardiomyocyte death are key mechanisms of I/R injury, but the source of reactive oxygen species (ROS) is unclear.

Purpose of the Study:

• To investigate the hypothesis that mitochondrial Complex I is the primary source of ROS during cardiac I/R injury.
• To determine the role of Complex I-mediated forward and reverse electron flows in I/R-induced oxidative stress and cardiomyocyte death.

Main Methods:

• Utilized a genetic mouse model with heart-specific knockout of Ndufs4, a Complex I subunit (Ndufs4H-/-).
• Assessed infarct size, cardiac function, and mitochondrial membrane potential in Ndufs4H-/- hearts subjected to I/R.
• Examined cardiomyocyte death, mitochondrial respiration, and NADH levels in isolated Ndufs4H-/- cardiomyocytes under I/R conditions.
• Employed pharmacological inhibitors of Complex I to block electron flow.

Main Results:

• Ndufs4H-/- hearts showed significantly reduced infarct size (20.9% vs 45.3% in wild type) and preserved function post-I/R.
• Isolated Ndufs4H-/- cardiomyocytes exhibited minimal cell death and preserved mitochondrial function during I/R.
• Ndufs4H-/- cardiomyocytes displayed slower NADH decline and inhibited mitochondrial flashes, indicating reduced Complex I activity.
• Pharmacological inhibition of Complex I protected against I/R-induced cardiomyocyte death.

Conclusions:

• Mitochondrial Complex I is a major source of ROS contributing to I/R injury in the mouse heart.
• Both forward and reverse electron flows through Complex I are implicated in oxidative cardiomyocyte death during reperfusion.
• Targeting Complex I activity offers a potential therapeutic strategy for mitigating I/R injury.