RRC ID 53840
Author Duncan OF, Granat L, Ranganathan R, Singh VK, Mazaud D, Fanto M, Chambers D, Ballard CG, Bateman JM.
Title Ras-ERK-ETS inhibition alleviates neuronal mitochondrial dysfunction by reprogramming mitochondrial retrograde signaling.
Journal PLoS Genet
Abstract Mitochondrial dysfunction activates the mitochondrial retrograde signaling pathway, resulting in large scale changes in gene expression. Mitochondrial retrograde signaling in neurons is poorly understood and whether retrograde signaling contributes to cellular dysfunction or is protective is unknown. We show that inhibition of Ras-ERK-ETS signaling partially reverses the retrograde transcriptional response to alleviate neuronal mitochondrial dysfunction. We have developed a novel genetic screen to identify genes that modify mitochondrial dysfunction in Drosophila. Knock-down of one of the genes identified in this screen, the Ras-ERK-ETS pathway transcription factor Aop, alleviates the damaging effects of mitochondrial dysfunction in the nervous system. Inhibition of Ras-ERK-ETS signaling also restores function in Drosophila models of human diseases associated with mitochondrial dysfunction. Importantly, Ras-ERK-ETS pathway inhibition partially reverses the mitochondrial retrograde transcriptional response. Therefore, mitochondrial retrograde signaling likely contributes to neuronal dysfunction through mis-regulation of gene expression.
Volume 14(7)
Pages e1007567
Published 2018-7-1
DOI 10.1371/journal.pgen.1007567
PMID 30059502
PMC PMC6085068
MeSH Animals Animals, Genetically Modified Behavior, Animal / physiology Disease Models, Animal Drosophila / physiology* Drosophila Proteins / genetics Drosophila Proteins / metabolism Extracellular Signal-Regulated MAP Kinases / metabolism Eye Proteins / genetics Eye Proteins / metabolism Female Gene Expression Profiling Gene Expression Regulation / physiology* Gene Knockdown Techniques Humans Leigh Disease / genetics Leigh Disease / pathology Male Mitochondria / metabolism* Mitochondrial Proteins / genetics Neurons / cytology Neurons / metabolism* Parkinsonian Disorders / genetics Parkinsonian Disorders / pathology Proto-Oncogene Proteins c-ets / metabolism Repressor Proteins / genetics Repressor Proteins / metabolism Signal Transduction / physiology* Ubiquitin-Protein Ligases / genetics ras Proteins / metabolism
IF 5.175
Times Cited 4
Drosophila 4217R-1 8676R-3 3166R-1 8056R-3 32677R-2 18623R-4 4004R-2 8451R-4 8895R-1 31125R-2 13399R-6 6632R-2 3166R-3