Miga mediated endoplasmic reticulum-mitochondria contact sites regulate neuronal homeostasis
- Zhejiang University, China
- Hangzhou Normal University College of Medicine, China
- Zhejiang University, China
Abstract
Endoplasmic reticulum (ER)–mitochondria contact sites (ERMCSs) are crucial for multiple cellular processes such as calcium signaling, lipid transport, mitochondrial dynamics, and autophagosome biogenesis. However, the molecular organization, functions, and regulation of ERMCS are not fully understood in higher eukaryotes. Also, the physiological roles of altered ERMCSs are not well defined. In this study, we found that Miga, a mitochondrion located protein, markedly increases ERMCSs and causes severe neurodegeneration upon overexpression in fly eyes. Miga interacts with an ER protein Vap33 through its FFAT-like motif and an amyotrophic lateral sclerosis (ALS) disease related Vap33 mutation considerably reduces its interaction with Miga. Multiple serine residues inside and near the Miga FFAT motif were phosphorylated, which is required for its interaction with Vap33 and Miga mediated ERMCS formation. The interaction between Vap33 and Miga promoted further phosphorylation of upstream serine/threonine clusters, which fine-tuned Miga activity. Protein kinases CKI and CaMKII contribute to Miga hyperphosphorylation. MIGA2, encoded by the miga mammalian ortholog, has conserved functions in mammalian cells. We propose a model that shows Miga interacts with Vap33 to mediate ERMCSs and excessive ERMCSs lead to neurodegeneration.
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Funding
National Natural Science Foundation of China (91754103)
- Chao Tong
National Natural Science Foundation of China (31622034)
- Chao Tong
National Natural Science Foundation of China (31571383)
- Chao Tong
National key research and developmental program of China (2017YFC1001100)
- Chao Tong
National key research and developmental program of China (2017YFC1001500)
- Chao Tong
Natural Science Foundation of Zhejiang Province (LR16C070001)
- Chao Tong
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Xu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Miga mediated endoplasmic reticulum-mitochondria contact sites regulate neuronal homeostasis
eLife 9:e56584.
https://doi.org/10.7554/eLife.56584
