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COPI-regulated mitochondria-ER contact site formation maintains axonal integrity

Maddison, Daniel C. ORCID:, Malik, Bilal, Amadio, Leonardo, Bis-Brewer, Dana M., Züchner, Stephan, Peters, Owen M. ORCID: and Smith, Gaynor A. ORCID: 2023. COPI-regulated mitochondria-ER contact site formation maintains axonal integrity. Cell Reports 42 (8) , 112883. 10.1016/j.celrep.2023.112883

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Coat protein complex I (COPI) is best known for its role in Golgi-endoplasmic reticulum (ER) trafficking, responsible for the retrograde transport of ER-resident proteins. The ER is crucial to neuronal function, regulating Ca2+ homeostasis and the distribution and function of other organelles such as endosomes, peroxisomes, and mitochondria via functional contact sites. Here we demonstrate that disruption of COPI results in mitochondrial dysfunction in Drosophila axons and human cells. The ER network is also disrupted, and the neurons undergo rapid degeneration. We demonstrate that mitochondria-ER contact sites (MERCS) are decreased in COPI-deficient axons, leading to Ca2+ dysregulation, heightened mitophagy, and a decrease in respiratory capacity. Reintroducing MERCS is sufficient to rescue not only mitochondrial distribution and Ca2+ uptake but also ER morphology, dramatically delaying neurodegeneration. This work demonstrates an important role for COPI-mediated trafficking in MERC formation, which is an essential process for maintaining axonal integrity.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Cell Press
ISSN: 2211-1247
Date of First Compliant Deposit: 17 July 2023
Date of Acceptance: 12 July 2023
Last Modified: 06 Jan 2024 04:41

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