PXD054020-1

PXD054020 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial L-2-hydroxyglutarate is a physiologic signaling metabolite
Description	L-2-hydroxyglutarate (L-2-HG) is a low-abundance metabolite in mammals, due to the mitochondrial enzyme L-2-HG dehydrogenase (L2HGDH), which oxidizes L-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation. In humans lacking L2HGDH activity, L-2-HG builds up, leading to L-2-HG aciduria, a rare childhood neurometabolic disorder. Thus, L-2-HG is classified as a toxic metabolite. Furthermore, L-2-HG is produced in response to hypoxia and electron transport chain (ETC) impairment. We investigated the regulation of L-2-HG levels, its impact on gene expression, and whether it has a physiological role in mice. Here, we report that elevated mitochondrial NADH/NAD+ triggers malate dehydrogenase 2 (MDH2) to produce L-2-HG from 2-OG. By contrast, L2HGDH converts L-2-HG to 2-OG in the mitochondrial matrix without requiring a functional ETC. Nascent mRNA expression analysis in mouse embryonic stem cells (mESCs) demonstrated that most genes were downregulated by elevated L-2-HG levels. To identify proteins involved in L-2-HG-dependent gene regulation, we used proteome integral solubility alteration assays (PISA), which showed that L-2-HG stabilizes the RNA demethylase FTO and H3K9 demethylases KDM4A/B/C in mESC nuclear extracts. The L-2-HG-dependent accumulation of m6A in mRNAs and H3K9me3 at the gene promoters negatively correlated with gene expression. Importantly, mitochondrial L2HGDH overexpression during early embryogenesis lowered basal L-2-HG levels and resulted in viable mice at birth but triggered reduced growth, impaired kidney development, and post-natal mortality. Thus, L-2-HG primarily downregulates gene expression and is a signaling metabolite necessary for mammalian development. These findings suggest that other previously considered toxic metabolites might also play physiological roles.
HostingRepository	PRIDE
AnnounceDate	2026-03-31
AnnouncementXML	Submission_2026-03-31_10:06:21.667.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jonathan Van Vranken
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2024-07-17 10:23:27	ID requested
⏵ 1	2026-03-31 10:06:22	announced

Dataset with its publication pending

submitter keyword: Mitochondria, Metabolism, 2-OG-dependent dioxygenases, metabolite signaling, gene expression regulation

Navdeep Chandel
contact affiliation	Department of Medicine, Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
contact email	nav@northwestern.edu
lab head
Jonathan Van Vranken
contact affiliation	Harvard Medical School
contact email	van@hms.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD054020
     1. Label: PRIDE project
     2. Name: Mitochondrial L-2-hydroxyglutarate is a physiologic signaling metabolite