BNIP3-Dependent Mitophagy Non-Autonomously Regulates Systemic Aging via NF-κB Suppression in Drosophila.

Abstract

Aging is a major risk factor for numerous diseases, including degenerative and metabolic disorders. Cumulative mitochondrial damage, elevated reactive oxygen species (ROS), and impaired mitophagy are hallmarks of aging. In this study, we generated a Drosophila version of the mito-SRAI reporter to monitor mitophagy in vivo and demonstrated an age-dependent decline in muscle mitophagy, accompanied by the accumulation of insoluble proteins, increased ROS levels, and mitochondrial damage. Overexpression of BNIP3 preserved muscle homeostasis by enhancing mitophagy, maintaining mitochondrial integrity, and suppressing ROS accumulation. Importantly, muscle-specific expression of BNIP3 in indirect flight muscles extended lifespan and alleviated age-associated neurodegenerative phenotypes, including protein aggregation, β-galactosidase accumulation, and pathological vacuolization in the brain. Mechanistically, BNIP3 inhibited ROS-mediated activation of Relish, thereby reducing expression of antimicrobial peptide (AMP) genes. These findings identify BNIP3 as a key regulator of aging that links mitochondrial quality control to systemic aging and neurodegeneration. Moreover, our results provide direct evidence of muscle-to-brain signaling, revealing a non-autonomous mechanism by which muscle mitophagy mitigates age-related neurodegeneration.