Rab5 and Alsin regulate stress-activated cytoprotective signaling on mitochondria

ELife
FoSheng HsuMarino Zerial

Abstract

Mitochondrial stress response is essential for cell survival, and damaged mitochondria are a hallmark of neurodegenerative diseases. Thus, it is fundamental to understand how mitochondria relay information within the cell. Here, by investigating mitochondrial-endosomal contact sites we made the surprising observation that the small GTPase Rab5 translocates from early endosomes to mitochondria upon oxidative stress. This process is reversible and accompanied by an increase in Rab5-positive endosomes in contact with mitochondria. Interestingly, activation of Rab5 on mitochondria depends on the Rab5-GEF ALS2/Alsin, encoded by a gene mutated in amyotrophic lateral sclerosis (ALS). Alsin-deficient human-induced pluripotent stem cell-derived spinal motor neurons are defective in relocating Rab5 to mitochondria and display increased susceptibility to oxidative stress. These findings define a novel pathway whereby Alsin catalyzes the assembly of the Rab5 endocytic machinery on mitochondria. Defects in stress-sensing by endosomes could be crucial for mitochondrial quality control during the onset of ALS.

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Citations

Feb 3, 2019·Disease Models & Mechanisms·Sandra Muñoz-BracerasRicardo Escalante
Apr 15, 2020·Nature Communications·Hampus Du RietzAnders Wittrup
Mar 12, 2020·Antioxidants & Redox Signaling·Inês Marques-AleixoJosé Magalhães
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Jul 12, 2019·Frontiers in Immunology·Kanako ShimizuShin-Ichiro Fujii
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Aug 7, 2021·Biomolecules·Juan A GodoyFrancisco J Muñoz

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Methods Mentioned

BETA
GTPases
GTPase
nucleotide exchange
confocal microscopy
electron microscopy
transmission electron microscopy
Fluorescence
Electrophoresis
PCR
transfection

Software Mentioned

Adobe Photoshop
Geneious
MotionTracking
Illustrator
Zeiss ZEN
Fiji
GraphPad Prism7

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