Decreasing pdzd8-mediated mito-ER contacts improves organismal fitness and mitigates A beta(42) toxicity

Mitochondria-ER contact sites (MERCs) orchestrate many important cellular functions including regulating mitochondria) quality control through mitophagy and mediating mitochondria) calcium uptake. Here, we identify and functionally characterize the Drosophila ortholog of the recently identified mammalian MERC protein, Pdzd8. We find that reducing pdzd8-mediated MERCs in neurons slows age-associated decline in locomotor activity and increases lifespan in Drosophila. The protective effects of pdzd8 knockdown in neurons correlate with an increase in mitophagy, suggesting that increased mitochondria) turnover may support healthy aging of neurons. In contrast, increasing MERCs by expressing a constitutive, synthetic ER-mitochondria tether disrupts mitochondria) transport and synapse formation, accelerates age-related decline in locomotion, and reduces lifespan. Although depletion of pdzd8 prolongs the survival of flies fed with mitochondria) toxins, it is also sufficient to rescue locomotor defects of a fly model of Alzheimer's disease expressing Amyloid beta(42) (A beta(42)). Together, our results provide the first in vivo evidence that MERCs mediated by the tethering protein pdzd8 play a critical role in the regulation of mitochondrial quality control and neuronal homeostasis.