PXD079746-1

PXD079746 is an original dataset announced via ProteomeXchange.

Title	Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity
Description	Of the ~1100 mitochondrial proteins, only a handful like PINK1 and ATFS-1 are known to stabilize and relocalize upon collapse of the proton motive force (PMF) to execute signaling roles. To systematically identify genes that increase exclusively at the protein level upon PMF collapse, we performed a joint proteomic and RNA-seq screen. The screen revealed 10 candidates (six mitochondrial), including the vitamin B12 chaperone MMADHC and cytosolic B12-dependent 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR). MMADHC is short-lived across cell types and we show that its levels increase with PMF collapse. MMADHC stabilization precedes PINK1 activation in a time course of increasing mtDNA depletion, suggesting greater sensitivity to PMF collapse. MMADHC accumulates in mitochondria with LONP1 inhibition but in the cytosol upon PMF collapse, likely due to mitochondrial import failure. Cytosol-stabilized MMADHC increases MTR levels and activity. Altogether, the mitochondrial PMF regulates the cytosolic B12-dependent MTR, integral to one-carbon metabolism, by controlling the stability and compartmentalization of the B12 chaperone MMADHC.
HostingRepository	PRIDE
AnnounceDate	2026-08-24
AnnouncementXML	Submission_2026-08-24_09:57:52.510.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Sneha Rath
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2026-06-15 18:51:41	ID requested
⏵ 1	2026-08-24 09:57:53	announced

Dataset with its publication pending

submitter keyword: proton motive force, MMADHC,vitamin B12, one carbon metabolism, metabolic compartmentalization

Vamsi K. Mootha
contact affiliation	HHMI and Department of Molecular Biology, Mass General Hospital Department of Systems Biology, Harvard Medical School Broad Institute of MIT & Harvard
contact email	vamsi_mootha@hms.harvard.edu
lab head
Sneha Rath
contact affiliation	Mass General Hospital, Harvard Medical School, Broad Institute
contact email	write2sr1224@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD079746
     1. Label: PRIDE project
     2. Name: Mitochondrial depolarization stabilizes the vitamin B12 chaperone MMADHC in the cytosol to increase MTR activity