PXD047327

PXD047327 is an original dataset announced via ProteomeXchange.

Title	Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis
Description	Organelle transporters define metabolic compartmentalization and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that SLC25A39, a mitochondrial transporter critical for mitochondrial glutathione uptake, is a short-lived protein under dual regulation at the protein level. Co-immunoprecipitation mass spectrometry and CRISPR KO in cells identified that mitochondrial m-AAA protease AFG3L2 is responsible for degrading SLC25A39 through the matrix loop 1. SLC25A39 senses mitochondrial iron-sulfur cluster using four matrix cysteine residues and inhibits its degradation. SLC25A39 protein regulation is robust in developing and mature neurons. This dual transporter regulation, by protein quality control and metabolic sensing, allows modulating mitochondrial glutathione level in response to iron homeostasis, opening new avenues to explore regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.
HostingRepository	PRIDE
AnnounceDate	2025-03-19
AnnouncementXML	Submission_2025-03-19_13:50:39.013.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	TuKiet Lam
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-28 05:32:44	ID requested
⏵ 1	2025-03-19 13:50:39	announced

10.1016/j.molcel.2023.12.008;

Shi X, DeCiucis M, Grabinska KA, Kanyo J, Liu A, Lam TT, Shen H, Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis. Mol Cell, 84(4):802-810.e6(2024) [pubmed]

submitter keyword: glutathione, protein quality control, AFG3L2,Mitochondrial transporter, iron, SLC25A39

TuKiet Lam
contact affiliation	Keck MS & Proteomics Resource Yale School of Medicine
contact email	tukiet.lam@yale.edu
lab head
TuKiet Lam
contact affiliation	Yale University
contact email	tukiet.lam@yale.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD047327
     1. Label: PRIDE project
     2. Name: Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis