RRC ID 51426
Author Kaufman DM, Wu X, Scott BA, Itani OA, Van Gilst MR, Bruce JE, Crowder CM.
Title Ageing and hypoxia cause protein aggregation in mitochondria.
Journal Cell Death Differ
Abstract Aggregation of cytosolic proteins is a pathological finding in disease states, including ageing and neurodegenerative diseases. We have previously reported that hypoxia induces protein misfolding in Caenorhabditis elegans mitochondria, and electron micrographs suggested protein aggregates. Here, we seek to determine whether mitochondrial proteins actually aggregate after hypoxia and other cellular stresses. To enrich for mitochondrial proteins that might aggregate, we performed a proteomics analysis on purified C. elegans mitochondria to identify relatively insoluble proteins under normal conditions (110 proteins identified) or after sublethal hypoxia (65 proteins). A GFP-tagged mitochondrial protein (UCR-11 - a complex III electron transport chain protein) in the normally insoluble set was found to form widespread aggregates in mitochondria after hypoxia. Five other GFP-tagged mitochondrial proteins in the normally insoluble set similarly form hypoxia-induced aggregates. Two GFP-tagged mitochondrial proteins from the soluble set as well as a mitochondrial-targeted GFP did not form aggregates. Ageing also resulted in aggregates. The number of hypoxia-induced aggregates was regulated by the mitochondrial unfolded protein response (UPRmt) master transcriptional regulator ATFS-1, which has been shown to be hypoxia protective. An atfs-1(loss-of-function) mutant and RNAi construct reduced the number of aggregates while an atfs-1(gain-of-function) mutant increased aggregates. Our work demonstrates that mitochondrial protein aggregation occurs with hypoxic injury and ageing in C. elegans. The UPRmt regulates aggregation and may protect from hypoxia by promoting aggregation of misfolded proteins.
Volume 24(10)
Pages 1730-1738
Published 2017-10-1
DOI 10.1038/cdd.2017.101
PII cdd2017101
PMID 28644434
PMC PMC5596417
MeSH Aging Animals Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / metabolism Mitochondria / metabolism* Mitochondrial Proteins / metabolism* Neurodegenerative Diseases / metabolism Oxygen / metabolism Transcription Factors / metabolism Unfolded Protein Response / physiology
IF 10.717
Times Cited 13
C.elegans tm4919