PT  - JOURNAL ARTICLE
AU  - Hewitt, Victoria L
AU  - Miller-Fleming, Leonor
AU  - Twyning, Madeleine J
AU  - Andreazza, Simonetta
AU  - Mattedi, Francesca
AU  - Prudent, Julien
AU  - Polleux, Franck
AU  - Vagnoni, Alessio
AU  - Whitworth, Alexander J
TI  - Decreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ<sub>42</sub> toxicity
AID  - 10.26508/lsa.202201531
DP  - 2022 Nov 01
TA  - Life Science Alliance
PG  - e202201531
VI  - 5
IP  - 11
4099  - http://www.life-science-alliance.org/content/5/11/e202201531.short
4100  - http://www.life-science-alliance.org/content/5/11/e202201531.full
SO  - Life Sci. Alliance2022 Nov 01; 5
AB  - Mitochondria-ER contact sites (MERCs) orchestrate many important cellular functions including regulating mitochondrial quality control through mitophagy and mediating mitochondrial 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 mitochondrial turnover may support healthy aging of neurons. In contrast, increasing MERCs by expressing a constitutive, synthetic ER–mitochondria tether disrupts mitochondrial transport and synapse formation, accelerates age-related decline in locomotion, and reduces lifespan. Although depletion of pdzd8 prolongs the survival of flies fed with mitochondrial toxins, it is also sufficient to rescue locomotor defects of a fly model of Alzheimer’s disease expressing Amyloid β42 (Aβ42). 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.