TY - JOUR
T1 - MPST sulfurtransferase maintains mitochondrial protein import and cellular bioenergetics to attenuate obesity
AU - Katsouda, Antonia
AU - Valakos, Dimitrios
AU - Dionellis, Vasilios S.
AU - Bibli, Sofia Iris
AU - Akoumianakis, Ioannis
AU - Karaliota, Sevasti
AU - Zuhra, Karim
AU - Fleming, Ingrid
AU - Nagahara, Noriyuki
AU - Havaki, Sophia
AU - Gorgoulis, Vassilis G.
AU - Thanos, Dimitris
AU - Antoniades, Charalambos
AU - Szabo, Csaba
AU - Papapetropoulos, Andreas
N1 - Funding Information:
The authors would like to thank Dr. Apostolos Klinakis (BRFAA, Athens, Greece) for the rederivation of Mpst−/− mice, Dr. David J. Fulton (Augusta University, Augusta, GA) for donating the HAHIF1α P402A/P564A-pcDNA3 plasmid, Dr. Ileana Badi (University of Oxford, Oxford, UK) for technical support in the study with the human samples, and Dr. Paraskevi Koutsoudaki (National and Kapodistrian University of Athens, Athens, Greece) for tissue processing for EM. This research has been cofinanced by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH– CREATE—INNOVATE (project code: T2EΔK-00843; to A. Papapetropoulos), by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (project number: HFRI-FM17-886), by the Hellenic Institute for the Study of Sepsis (to A. Papapetropoulos), by the Hellenic State Scholarship Foundation IKY-Siemens Research Projects of Excellence (11/3056 to A. Papapetropoulos and A. Katsouda), by a scholarship to A. Katsouda by the Hellenic Foundation for Research and Innovation, by the Deutsche Forschungsgemeinschaft (CRC1366/1 B1 Project # 39404578 to I. Fleming and S.-I. Bibli, and the Cardio-Pulmonary Institute, EXC 2026, Project ID: 390649896), and by the Swiss National Research Foundation (SNSF 31003A_179434) to C. Szabo.
Funding Information:
Disclosures: I. Fleming reported grants from Deutsche For-schungsgemeinschaft during the conduct of the study. C. Anto-niades 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.
Funding Information:
This research has been cofinanced by the European Regional Development Fund of the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH– CREATE—INNOVATE (project code: T2EΔK-00843; to A. Pa-papetropoulos), by the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (project number: HFRI-FM17-886), by the Hellenic Institute for the Study of Sepsis (to A. Papapetropoulos), by the Hellenic State Scholarship Foundation IKY-Siemens Research Projects of Excellence (11/3056 to A. Papapetropoulos and A. Katsouda), by a scholarship to A. Katsouda by the Hellenic Foundation for Research and Innovation, by the Deutsche Forschungsgemeinschaft (CRC1366/1 B1 Project # 39404578 to I. Fleming and S.-I. Bibli, and the Cardio-Pulmonary Institute, EXC 2026, Project ID: 390649896), and by the Swiss National Research Foundation (SNSF 31003A_179434) to C. Szabo.
Publisher Copyright:
© 2022 Katsouda et al.
PY - 2022/7/4
Y1 - 2022/7/4
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20211894
DO - 10.1084/jem.20211894
M3 - Article
C2 - 35616614
AN - SCOPUS:85130853499
SN - 0022-1007
VL - 219
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
M1 - e20211894
ER -