Early mitophagy defects and impaired mitochondrial energy metabolism drive target organ damage progression: Lessons from the Fabry heart.

Early mitophagy defects in a humanized Fabry disease mouse model (R301Q-Tg/GLA knockout) drive age-progressive mitochondrial dysfunction, energetic failure, and diastolic dysfunction.

• Why it matters: Impaired energy metabolism is linked to organ damage, but how it progresses in Fabry cardiomyopathy beyond Gb3 storage remains unclear.
• What they did: The study assessed mitophagy, mitochondrial respiration, reactive oxygen species, and lysosomal dysfunction across humanized FD mice, embryonic fibroblasts, and neonatal/adult cardiomyocytes, then tested L-arginine.
• The result: Defects progressed with age, causing dysfunctional mitochondrial accumulation, apoptosis, cardiac hypertrophy, and diastolic dysfunction, while L-arginine prevented cardiac abnormalities via NO/PGC-1α–dependent mitochondrial rescue.