Neuronal induction of BNIP3-mediated mitophagy slows systemic aging in Drosophila

Abstract The effects of aging on the brain are widespread and present at both the cellular and functional level. Mitochondrial dysfunction(definition) is a hallmark of brain aging, but, the interplay between mitochondrial quality control, neuronal aging, and organismal health is not well understood. Here, we show that aging leads to a decline in mitochondrial autophagy(definition) (mitophagy) in the Drosophila brain and a concomitant increase in mitochondrial content. We find that induction of BCL2-interacting protein 3 (BNIP3), a mitochondrial outer membrane protein, in the adult nervous system induces mitophagy and prevents the accumulation of dysfunctional mitochondria in the aged brain. Importantly, neuronal induction of BNIP3-mediated mitophagy increases organismal longevity and healthspan(definition). Furthermore, neuronal BNIP3-mediated mitophagy improves mitochondrial homeostasis and proteostasis(definition) in aged muscle, indicating cell non-autonomous effects. In addition, neuronal BNIP3-mediated mitophagy improves intestinal homeostasis in aged flies. Our findings identify BNIP3 as a novel therapeutic target to counteract brain aging and prolong overall organismal health with age.