Given the clinical, economic, and societal impact of obesity, unraveling the mechanisms of adipose tissue expansion remains of fundamental significance. We previously showed that white adipose tissue (WAT) levels of 3-mercaptopyruvate sulfurtransferase (MPST), a mitochondrial cysteine-catabolizing enzyme that yields pyruvate and sulfide species, are downregulated in obesity. Here, we report that Mpst deletion results in fat accumulation in mice fed a high-fat diet (HFD) through transcriptional and metabolic maladaptation. Mpst-deficient mice on HFD exhibit increased body weight and inguinal WAT mass, reduced metabolic rate, and impaired glucose/insulin tolerance. At the molecular level, Mpst ablation activates HIF1α, downregulates subunits of the translocase of outer/inner membrane (TIM/TOM) complex, and impairs mitochondrial protein import. MPST deficiency suppresses the TCA cycle, oxidative phosphorylation, and fatty acid oxidation, enhancing lipid accumulation. Sulfide donor administration to obese mice reverses the HFD-induced changes. These findings reveal the significance of MPST for white adipose tissue biology and metabolic health and identify a potential new therapeutic target for obesity.
MPST sulfurtransferase maintains mitochondrial protein import and cellular bioenergetics to attenuate obesity
Disclosures: I. Fleming reported grants from Deutsche Forschungsgemeinschaft during the conduct of the study. C. Antoniades reported personal fees from Caristo Diagnostics outside the submitted work. A. Papapetropoulos reported non-financial support from Sulfagenic, Inc. during the conduct of the study, and “other” from Sulfagenix, Inc. and grants from Antibe Therapeutics, Inc. outside the submitted work; in addition, A. Papapetropoulos is a member of the Scientific Advisory Board of Sulfagenix, Inc. No other disclosures were reported.
- Award Id(s): 11/3056
- Award Id(s): CRC1366/1
- Award Id(s): EXC 2026
- Award Id(s): 31003A_179434
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Antonia Katsouda, Dimitrios Valakos, Vasilios S. Dionellis, Sofia-Iris Bibli, Ioannis Akoumianakis, Sevasti Karaliota, Karim Zuhra, Ingrid Fleming, Noriyuki Nagahara, Sophia Havaki, Vassilis G. Gorgoulis, Dimitris Thanos, Charalambos Antoniades, Csaba Szabo, Andreas Papapetropoulos; MPST sulfurtransferase maintains mitochondrial protein import and cellular bioenergetics to attenuate obesity. J Exp Med 4 July 2022; 219 (7): e20211894. doi: https://doi.org/10.1084/jem.20211894
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