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Defending stressed mitochondria: uncovering the role of MUL1 in suppressing neuronal mitophagy.

Authors
  • Puri, Rajat1
  • Cheng, Xiu-Tang1
  • Lin, Mei-Yao1
  • Huang, Ning1
  • Sheng, Zu-Hang1
  • 1 Synaptic Function Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Type
Published Article
Journal
Autophagy
Publisher
Landes Bioscience
Publication Date
Nov 07, 2019
Pages
1–3
Identifiers
DOI: 10.1080/15548627.2019.1687216
PMID: 31679452
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Chronic mitochondrial stress is associated with major neurodegenerative diseases; and thus, the recovery of those mitochondria constitutes a critical step of energy maintenance in early stages of neurodegeneration. Our recent study provides the first lines of evidence showing that the MUL1-MFN2 pathway acts as an early checkpoint to maintain mitochondrial integrity by regulating mitochondrial morphology and interplay with the endoplasmic reticulum (ER). This mechanism ensures that degradation through mitophagy is restrained in neurons under early stress conditions. MUL1 deficiency increases MFN2 activity, triggering the first phase of mitochondrial hyperfusion and acting as an antagonist of ER-mitochondria (ER-Mito) tethering. Reduced ER-Mito interplay enhances the cytoplasmic Ca2+ load that induces the DNM1L/Drp1-dependent second phase of mitochondrial fragmentation and mitophagy. Our study provides new mechanistic insights into neuronal mitochondrial maintenance under stress conditions. Identifying this pathway is particularly relevant because chronic mitochondrial dysfunction and altered ER-Mito contacts have been reported in major neurodegenerative diseases.

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