RRC ID 45585
Author Köhler F, Müller-Rischart AK, Conradt B, Rolland SG.
Title The loss of LRPPRC function induces the mitochondrial unfolded protein response.
Journal Aging (Albany NY)
Abstract The inactivation of the LRPPRC gene, which has previously been associated with the neurodegenerative French Canadian Leigh Syndrome, results in a decrease in the production of mitochondria-encoded subunits of complex IV, thereby causing a reduction in complex IV activity. Previously we have shown that reducing complex IV activity triggers a compensatory and conserved mitochondrial hyperfusion response. We now demonstrate that LRPPRC knock-down in mammalian cells leads to an imbalance between mitochondria-encoded and nuclear-encoded subunits of complex IV and that this imbalance triggers the mitochondrial unfolded protein response (UPR(mt)). The inactivation of the LRPPRC-like gene mma-1 in C. elegans also induces UPR(mt), which demonstrates that this response is conserved. Furthermore, we provide evidence that mitochondrial hyperfusion and UPR(mt) are coordinated but mediated by genetically distinct pathways. We propose that in the context of LRPPRC mma-1 knock-down, mitochondrial hyperfusion helps to transiently maintain mitochondrial ATP production while UPR(mt) participates in the restoration of mitochondrial proteostasis. Mitochondrial proteostasis is not only critical in pathophysiology but also during aging, as proteotoxic stress has been shown to increase with age. Therefore, we speculate that the coordination of these two mitochondrial stress responses plays a more global role in mitochondrial proteostasis.
Volume 7(9)
Pages 701-17
Published 2015-9-1
DOI 10.18632/aging.100812
PII 100812
PMID 26412102
PMC PMC4600627
MeSH Adenosine Triphosphate / biosynthesis Aging / genetics Animals Caenorhabditis elegans Caenorhabditis elegans Proteins / genetics* Caenorhabditis elegans Proteins / metabolism* Gene Knockdown Techniques Humans Mitochondria / genetics* Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism Neoplasm Proteins / genetics* Neoplasm Proteins / metabolism* RNA, Small Interfering / pharmacology Transfection Unfolded Protein Response / genetics*
IF 4.831
Times Cited 9
C.elegans tm4525 tm1133