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dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective
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Journal Article
dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective
2017
Overview
Neurons rely on mitochondria as their preferred source of energy. Mutations in
PINK1
and
PARKIN
cause neuronal death in early-onset Parkinson’s disease (PD), thought to be due to mitochondrial dysfunction. In
Drosophila pink1
and
parkin
mutants, mitochondrial defects lead to the compensatory upregulation of the mitochondrial one-carbon cycle metabolism genes by an unknown mechanism. Here we uncover that this branch is triggered by the activating transcription factor 4 (ATF4). We show that ATF4 regulates the expression of one-carbon metabolism genes
SHMT2
and
NMDMC
as a protective response to mitochondrial toxicity. Suppressing
Shmt2
or
Nmdmc
caused motor impairment and mitochondrial defects in flies. Epistatic analyses showed that suppressing the upregulation of
Shmt2
or
Nmdmc
deteriorates the phenotype of
pink1
or
parkin
mutants. Conversely, the genetic enhancement of these one-carbon metabolism genes in
pink1
or
parkin
mutants was neuroprotective. We conclude that mitochondrial dysfunction caused by mutations in the Pink1/Parkin pathway engages ATF4-dependent activation of one-carbon metabolism as a protective response. Our findings show a central contribution of ATF4 signalling to PD that may represent a new therapeutic strategy. A video abstract for this article is available at
https://youtu.be/cFJJm2YZKKM
.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38/39
/ 38/89
/ 64/24
/ Acids
/ Activating Transcription Factor 4 - antagonists & inhibitors
/ Activating Transcription Factor 4 - genetics
/ Activating Transcription Factor 4 - metabolism
/ Animals
/ Biomedical and Life Sciences
/ Carbon
/ Drosophila Proteins - antagonists & inhibitors
/ Drosophila Proteins - genetics
/ Drosophila Proteins - metabolism
/ Enzymes
/ Glycine Hydroxymethyltransferase - metabolism
/ Insects
/ Kinases
/ Methylenetetrahydrofolate Dehydrogenase (NADP) - metabolism
/ Mutation
/ Parkinson Disease - metabolism
/ Parkinson Disease - pathology
/ Protein-Serine-Threonine Kinases - genetics
/ Protein-Serine-Threonine Kinases - metabolism
/ Proteins
/ RNA, Small Interfering - metabolism
/ Toxicity
/ Ubiquitin-Protein Ligases - genetics
