Mitochondrial GSNOR Alleviates Cardiac Dysfunction via ANT1 Denitrosylation

Area of Science:

• Cardiovascular Biology
• Mitochondrial Medicine
• Enzymology

Background:

• Cytoplasmic S-nitrosoglutathione reductase (GSNOR) is known for cardiac protection.
• The role and localization of GSNOR in other organelles, particularly mitochondria, remain unexplored.
• This study investigates the novel role of mitochondrial GSNOR in cardiac remodeling and heart failure (HF).

Purpose of the Study:

• To determine the subcellular localization of GSNOR in cardiac tissue.
• To elucidate the functional impact of mitochondrial GSNOR on cardiac remodeling and heart failure.
• To identify the molecular mechanisms underlying mitochondrial GSNOR's effects on cardiac function.

Main Methods:

• GSNOR localization confirmed via cellular fractionation, immunofluorescence, and electron microscopy.
• Mitochondrial GSNOR overexpression achieved using AAV9 vectors; cardiac-specific knockout mice used for functional studies.
• Adenine nucleotide translocase 1 (ANT1) S-nitrosylation identified using mass spectrometry.

Main Results:

• GSNOR expression is reduced in human HF cardiac tissue and cardiac-specific knockout mice exhibit exacerbated remodeling.
• Mitochondrial GSNOR deficiency impairs cardiomyocyte function; restoration improves mitochondrial function and cardiac performance in HF models.
• GSNOR directly denitrosylates ANT1 at C160, and this interaction is crucial for maintaining mitochondrial homeostasis and mitophagy.

Conclusions:

• A novel mitochondrial GSNOR species was identified, playing a critical role in cardiac homeostasis.
• Mitochondrial GSNOR maintains mitochondrial function via ANT1 denitrosylation.
• Targeting mitochondrial GSNOR presents a promising therapeutic strategy for heart failure.