Cited by 54Mitochondrial Function and PathologyAutophagy in Disease and TherapySulfur Compounds in Biology

Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis

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Shi, Xiaojian, DeCiucis, Marisa, Grabinska, Kariona A., Kanyo, Jean, Liu, Adam, Lam, Tukiet T., Shen, Hongying·2024·Molecular Cell

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Abstract

Organelle transporters define metabolic compartmentalization, and how this metabolite transport process can be modulated is poorly explored. Here, we discovered that human 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 knockout (KO) in mammalian 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 avenues for exploring regulation of metabolic compartmentalization. Neuronal SLC25A39 regulation connects mitochondrial protein quality control, glutathione, and iron homeostasis, which were previously unrelated biochemical features in neurodegeneration.

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Authors
Shi, X., DeCiucis, M., Grabinska, K. A., Kanyo, J., Liu, A., Lam, T. T., & Shen, H.
Affiliations
Yale University (US)
Corresponding author
Shen, Hongying
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2024-02
Volume
84
Issue
4
Pages
802-810.e6
ISSN
1097-2765 (ISSN-L)
OpenAlex
W4390350694
Cited by
54
References
48
Citations by year
2026: 18 · 2025: 21 · 2024: 15
FWCI
4.81
Type
journal article
Language
en
Open access
Locations
  • Molecular Cell (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (S10OD018034, S10OD019967, S10OD02365101A1)
  • National Institute of General Medical Sciences (R35GM150619)
  • Office of the Director
  • Rita Allen Foundation
  • Yale University
  • Yale School of Medicine
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Sulfur Compounds in Biology
Keywords
AFG3L2, iron homeostasis, iron-sulfur clusters, protein degradation, protein quality control, metabolic compartmentation, neurodegeneration
MeSH terms
ATPases Associated with Diverse Cellular Activities, Animals, Glutathione, Homeostasis, Humans, Iron, Mammals, Mitochondria, Mitochondrial Proteins, Mitochondrial Membrane Transport Proteins, ATP-Dependent Proteases

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