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

Journal article


Maddison, D., Malik, B., Amadio, L., Bis-Brewer, D. M., Züchner, S., Peters, O. M. and Smith, G. A. 2023. COPI-regulated mitochondria-ER contact site formation maintains axonal integrity. Cell Reports. 42 (8), pp. 1-20. https://doi.org/10.1016/j.celrep.2023.112883
AuthorsMaddison, D., Malik, B., Amadio, L., Bis-Brewer, D. M., Züchner, S., Peters, O. M. and Smith, G. A.
Abstract

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.

KeywordsDrosophila; mito-ER contact; axon; neuron; MERCS-mitochondria-ER contact sites
Year2023
JournalCell Reports
Journal citation42 (8), pp. 1-20
PublisherCell Press
ISSN2211-1247
Digital Object Identifier (DOI)https://doi.org/10.1016/j.celrep.2023.112883
Output statusPublished
Publication dates
Online26 Jul 2023
Publication process dates
Deposited18 Sep 2023
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https://repository.derby.ac.uk/item/q038x/copi-regulated-mitochondria-er-contact-site-formation-maintains-axonal-integrity

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