Autoregulatory control of mitochondrial glutathione homeostasis

Yuyang Liu; Shanshan Liu; Anju Tomar; Frederick S. Yen; Gokhan Unlu; Nathalie Ropek; Ross A. Weber; Ying Wang; Artem Khan; Mark Gad; Junhui Peng; Erdem Terzi; Hanan Alwaseem; Alexandra E. Pagano; Søren Heissel; Henrik Molina; Benjamin Allwein; Timothy C. Kenny; Richard L. Possemato; Li Zhao; Richard K. Hite; Ekaterina V. Vinogradova; Sheref S. Mansy; Kıvanç Birsoy

doi:10.1126/SCIENCE.ADF4154

Autoregulatory control of mitochondrial glutathione homeostasis

Yuyang Liu
, Shanshan Liu
, Anju Tomar
, Frederick S. Yen
, Gokhan Unlu
, Nathalie Ropek
, Ross A. Weber
, Ying Wang
, Artem Khan
, Mark Gad
, Junhui Peng
, Erdem Terzi
, Hanan Alwaseem
, Alexandra E. Pagano
, Søren Heissel
, Henrik Molina
, Benjamin Allwein
, Timothy C. Kenny
, Richard L. Possemato
, Li Zhao

Richard K. Hite, Ekaterina V. Vinogradova, Sheref S. Mansy, Kıvanç Birsoy

Research output: Contribution to journal › Article › peer-review

123 Scopus citations

Abstract

Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. In this work, we focused on glutathione (GSH), a critical redox metabolite in mitochondria, and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by mitochondrial protease AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analyses identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 as essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.

Original language	English
Pages (from-to)	820-828
Number of pages	9
Journal	Science
Volume	382
Issue number	6672
DOIs	https://doi.org/10.1126/SCIENCE.ADF4154
State	Published - 17 Nov 2023
Externally published	Yes

Access to Document

10.1126/SCIENCE.ADF4154

Cite this

Liu, Y., Liu, S., Tomar, A., Yen, F. S., Unlu, G., Ropek, N., Weber, R. A., Wang, Y., Khan, A., Gad, M., Peng, J., Terzi, E., Alwaseem, H., Pagano, A. E., Heissel, S., Molina, H., Allwein, B., Kenny, T. C., Possemato, R. L., ... Birsoy, K. (2023). Autoregulatory control of mitochondrial glutathione homeostasis. Science, 382(6672), 820-828. https://doi.org/10.1126/SCIENCE.ADF4154

@article{1dc860cef98a45caa4a982b6c59f5605,

title = "Autoregulatory control of mitochondrial glutathione homeostasis",

abstract = "Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. In this work, we focused on glutathione (GSH), a critical redox metabolite in mitochondria, and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by mitochondrial protease AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analyses identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 as essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.",

author = "Yuyang Liu and Shanshan Liu and Anju Tomar and Yen, \{Frederick S.\} and Gokhan Unlu and Nathalie Ropek and Weber, \{Ross A.\} and Ying Wang and Artem Khan and Mark Gad and Junhui Peng and Erdem Terzi and Hanan Alwaseem and Pagano, \{Alexandra E.\} and S{\o}ren Heissel and Henrik Molina and Benjamin Allwein and Kenny, \{Timothy C.\} and Possemato, \{Richard L.\} and Li Zhao and Hite, \{Richard K.\} and Vinogradova, \{Ekaterina V.\} and Mansy, \{Sheref S.\} and Kıvan{\c c} Birsoy",

year = "2023",

month = nov,

day = "17",

doi = "10.1126/SCIENCE.ADF4154",

language = "English",

volume = "382",

pages = "820--828",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6672",

}

Liu, Y, Liu, S, Tomar, A, Yen, FS, Unlu, G, Ropek, N, Weber, RA, Wang, Y, Khan, A, Gad, M, Peng, J, Terzi, E, Alwaseem, H, Pagano, AE, Heissel, S, Molina, H, Allwein, B, Kenny, TC, Possemato, RL, Zhao, L, Hite, RK, Vinogradova, EV, Mansy, SS & Birsoy, K 2023, 'Autoregulatory control of mitochondrial glutathione homeostasis', Science, vol. 382, no. 6672, pp. 820-828. https://doi.org/10.1126/SCIENCE.ADF4154

TY - JOUR

T1 - Autoregulatory control of mitochondrial glutathione homeostasis

AU - Liu, Yuyang

AU - Liu, Shanshan

AU - Tomar, Anju

AU - Yen, Frederick S.

AU - Unlu, Gokhan

AU - Ropek, Nathalie

AU - Weber, Ross A.

AU - Wang, Ying

AU - Khan, Artem

AU - Gad, Mark

AU - Peng, Junhui

AU - Terzi, Erdem

AU - Alwaseem, Hanan

AU - Pagano, Alexandra E.

AU - Heissel, Søren

AU - Molina, Henrik

AU - Allwein, Benjamin

AU - Kenny, Timothy C.

AU - Possemato, Richard L.

AU - Zhao, Li

AU - Hite, Richard K.

AU - Vinogradova, Ekaterina V.

AU - Mansy, Sheref S.

AU - Birsoy, Kıvanç

PY - 2023/11/17

Y1 - 2023/11/17

N2 - Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. In this work, we focused on glutathione (GSH), a critical redox metabolite in mitochondria, and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by mitochondrial protease AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analyses identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 as essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.

AB - Mitochondria must maintain adequate amounts of metabolites for protective and biosynthetic functions. However, how mitochondria sense the abundance of metabolites and regulate metabolic homeostasis is not well understood. In this work, we focused on glutathione (GSH), a critical redox metabolite in mitochondria, and identified a feedback mechanism that controls its abundance through the mitochondrial GSH transporter, SLC25A39. Under physiological conditions, SLC25A39 is rapidly degraded by mitochondrial protease AFG3L2. Depletion of GSH dissociates AFG3L2 from SLC25A39, causing a compensatory increase in mitochondrial GSH uptake. Genetic and proteomic analyses identified a putative iron-sulfur cluster in the matrix-facing loop of SLC25A39 as essential for this regulation, coupling mitochondrial iron homeostasis to GSH import. Altogether, our work revealed a paradigm for the autoregulatory control of metabolic homeostasis in organelles.

UR - https://www.scopus.com/pages/publications/85177103865

U2 - 10.1126/SCIENCE.ADF4154

DO - 10.1126/SCIENCE.ADF4154

M3 - Article

C2 - 37917749

AN - SCOPUS:85177103865

SN - 0036-8075

VL - 382

SP - 820

EP - 828

JO - Science

JF - Science

IS - 6672

ER -

Autoregulatory control of mitochondrial glutathione homeostasis

Abstract

Access to Document

Fingerprint

Cite this