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Decreasing pdzd8-mediated mitochondrial-ER contacts in neurons improves fitness by increasing mitophagy

View ORCID ProfileVictoria L. Hewitt, Leonor Miller-Fleming, Simonetta Andreazza, Francesca Mattedi, Julien Prudent, Franck Polleux, Alessio Vagnoni, Alexander J. Whitworth
doi: https://doi.org/10.1101/2020.11.14.382861
Victoria L. Hewitt
1Department of Neuroscience, Columbia University Medical Center New York, NY, USA
3MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
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  • ORCID record for Victoria L. Hewitt
  • For correspondence: vlh2118@columbia.edu
Leonor Miller-Fleming
3MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
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Simonetta Andreazza
3MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
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Francesca Mattedi
4Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, IoPPN, King’s College London, London, UK
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Julien Prudent
3MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
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Franck Polleux
1Department of Neuroscience, Columbia University Medical Center New York, NY, USA
2Mortimer B. Zuckerman Mind Brain Behavior Institute, New York, NY, USA
5Kavli Institute for Brain Sciences, Columbia University Medical Center, New York, NY, USA
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Alessio Vagnoni
4Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, IoPPN, King’s College London, London, UK
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Alexander J. Whitworth
3MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
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Abstract

The complex cellular architecture of neurons combined with their longevity makes maintaining a healthy mitochondrial network particularly important and challenging. One of the many roles of mitochondrial-ER contact sites (MERCs) is to mediate mitochondrial quality control through regulating mitochondrial turn over. Pdzd8 is a newly discovered MERC protein, the organismal functions of which have not yet been explored. Here we identify and provide the first functional characterization of the Drosophila melanogaster ortholog of 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. We also show that depletion of pdzd8 rescues the locomotor defects characterizing an Alzheimer’s disease (AD) fly model over-expressing Amyloidβ1–42 (Aβ42) and prolongs the survival of flies fed with mitochondrial toxins. 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted November 15, 2020.
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Decreasing pdzd8-mediated mitochondrial-ER contacts in neurons improves fitness by increasing mitophagy
Victoria L. Hewitt, Leonor Miller-Fleming, Simonetta Andreazza, Francesca Mattedi, Julien Prudent, Franck Polleux, Alessio Vagnoni, Alexander J. Whitworth
bioRxiv 2020.11.14.382861; doi: https://doi.org/10.1101/2020.11.14.382861
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Decreasing pdzd8-mediated mitochondrial-ER contacts in neurons improves fitness by increasing mitophagy
Victoria L. Hewitt, Leonor Miller-Fleming, Simonetta Andreazza, Francesca Mattedi, Julien Prudent, Franck Polleux, Alessio Vagnoni, Alexander J. Whitworth
bioRxiv 2020.11.14.382861; doi: https://doi.org/10.1101/2020.11.14.382861

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