MPST sulfurtransferase maintains mitochondrial protein import and cellular bioenergetics to attenuate obesity.

Abstract

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.

• Authors: 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
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 219 Issue 7 (07 04 2022) ISSN: 1540-9538 [Electronic] United States
• PMID: 35616614 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 Katsouda et al.

Chemical References

• Mitochondrial Proteins
• Sulfides
• Sulfurtransferases

Topics

• Animals
• Diet, High-Fat
• Energy Metabolism
• Glucose Intolerance
• Mice
• Mice, Inbred C57BL
• Mitochondrial Proteins (metabolism)
• Obesity (metabolism)
• Sulfides
• Sulfurtransferases (metabolism)