PXD018839

PXD018839 is an original dataset announced via ProteomeXchange.

Title	Defective NADPH Production in Mitochondrial Disease Complex I Causes Inflammation and Cell Death
Description	Electron transport chain (ETC) defects occurring from mitochondrial disease mutations compromise ATP synthesis and render cells vulnerable to nutrient and oxidative stress conditions. This bioenergetic failure is thought to underlie pathologies associated with mitochondrial diseases. However, the precise metabolic processes resulting from a defective mitochondrial ETC that compromise cell viability under stress conditions are not entirely understood. We design a whole genome gain-of-function CRISPR activation screen using human mitochondrial disease complex I (CI) mutant cells to identify genes whose increased function rescue glucose restriction-induced cell death. The top hit of the screen is the cytosolic Malic Enzyme (ME1), that is sufficient to enable survival and proliferation of CI mutant cells under nutrient stress conditions. Unexpectedly, this metabolic rescue is independent of increased ATP synthesis through glycolysis or oxidative phosphorylation, but dependent on ME1-produced NADPH and glutathione (GSH). Survival upon nutrient stress or pentose phosphate pathway (PPP) inhibition depends on compensatory NADPH production through the mitochondrial one-carbon metabolism that is severely compromised in CI mutant cells. Importantly, this defective CI-dependent decrease in mitochondrial NADPH production pathway or genetic ablation of SHMT2 causes strong inflammatory cytokine signatures associated with redox dependent induction of ASK1 and activation of stress kinases p38 and JNK. These studies find that a major defect of CI deficiencies is decreased mitochondrial one-carbon NADPH production that is associated with increased inflammation and cell death.
HostingRepository	PRIDE
AnnounceDate	2021-09-09
AnnouncementXML	Submission_2021-09-08_19:30:12.566.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mark Jedrychowski
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-04-27 21:58:07	ID requested
⏵ 1	2021-09-08 19:30:13	announced

Balsa E, Perry EA, Bennett CF, Jedrychowski M, Gygi SP, Doench JG, Puigserver P, Defective NADPH production in mitochondrial disease complex I causes inflammation and cell death. Nat Commun, 11(1):2714(2020) [pubmed]

submitter keyword: Human, Mitochondria, TMT, Nature Communication Manuscript: NCOMMS-19-24220B

Pere Puigserver
contact affiliation	Dana Farber Cancer Institute: Dept. of Cancer Biology Harvard Medical School: Department of Cell Biology
contact email	Pere_Puigserver@dfci.harvard.edu
lab head
Mark Jedrychowski
contact affiliation	Harvard Medical School
contact email	mark_jedrychowski@hms.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD018839
     1. Label: PRIDE project
     2. Name: Defective NADPH Production in Mitochondrial Disease Complex I Causes Inflammation and Cell Death