Salt-derived lysosome impairment provokes tubular damage via mitochondrial quality control defects

Excessive salt consumption is associated with an increased risk of progressive kidney injury and heart failure. Understanding the mechanistic basis of high sodium (HS)-induced organ dysfunction is crucial for the development of novel pharmacotherapeutics. Herein, we show that exposure of kidney tubules to HS impairs lysosomal function via a reduction in V-ATPase expression, leading to dysregulation of mitophagy. HS also reduces mitofilin and DRP-1 in kidney tubular cells, thereby impairing mitochondrial dynamics, quality and function. Decreased renal levels of mitofilin are observed in patients with various kidney diseases and correlates with kidney dysfunction. Administration of mitochonic aid-5 (MA-5) preserves lysosomal function via restoration of V-ATPase and attenuates mitophagy, mitochondrial morphology and quality. MA-5 treatment also improves kidney and cardiac function in uninephrectomized mice administered deoxycorticosterone acetate with HS overload. Our present study suggests that MA-5 may play a protective role against HS-induced organ damages in the kidneys and hearts.