MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes

Chunyan Wu, Tongtong Wang, Adhideb Ghosh, Fen Long, Anand Kumar Sharma, Tina Dahlby, Falko Noé, Ilenia Severi, Georgia Colleluori, Saverio Cinti, Antonio Giordano, Lianggong Ding, Radhika Khandelwal, Sarantos Kostidis, Martin Giera, Lucia Balazova, Vincent Gardeux, Laith Abu-Nawwas, Bart Deplancke, Sabita Chourasia, Sandra Kleiner, Bradford S. Hamilton, Juan Manuel Alcántara Alcántara, Jonatan R. Ruiz, Matthias Blüher, Anton Pekcec, Miroslav Balaz, Atan Gross, Heike Neubauer and Christian Wolfrum ()
Additional contact information
Chunyan Wu: ETH Zürich
Tongtong Wang: ETH Zürich
Adhideb Ghosh: ETH Zürich
Fen Long: ETH Zürich
Anand Kumar Sharma: ETH Zürich
Tina Dahlby: ETH Zürich
Falko Noé: ETH Zürich
Ilenia Severi: Marche Polytechnic University
Georgia Colleluori: Marche Polytechnic University
Saverio Cinti: Marche Polytechnic University
Antonio Giordano: Marche Polytechnic University
Lianggong Ding: ETH Zürich
Radhika Khandelwal: ETH Zürich
Sarantos Kostidis: Leiden University Medical Center
Martin Giera: Leiden University Medical Center
Lucia Balazova: Slovak Academy of Sciences
Vincent Gardeux: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Laith Abu-Nawwas: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Bart Deplancke: Ecole Polytechnique Fédérale de Lausanne (EPFL)
Sabita Chourasia: Weizmann Institute of Science
Sandra Kleiner: Boehringer Ingelheim Pharma GmbH & Co. KG
Bradford S. Hamilton: Boehringer Ingelheim Pharma GmbH & Co. KG
Juan Manuel Alcántara Alcántara: University of Granada
Jonatan R. Ruiz: University of Granada
Matthias Blüher: Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig
Anton Pekcec: Boehringer Ingelheim Pharma GmbH & Co. KG
Miroslav Balaz: Slovak Academy of Sciences
Atan Gross: Weizmann Institute of Science
Heike Neubauer: Boehringer Ingelheim Pharma GmbH & Co. KG
Christian Wolfrum: ETH Zürich

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Metabolic disorders, including obesity and metabolic-associated steatohepatitis, arise from a chronic energy surplus. Thus, enhancing energy dissipation through increased respiration holds significant therapeutic potential for metabolic disorders. Through a comprehensive analysis of human and murine adipose tissues, along with a functional screen, we identify mitochondrial carrier homolog 2, a mitochondrial outer membrane protein, as a pivotal regulator of mitochondrial metabolism. Intriguingly, its expression in adipose tissue is a strong determinant of obesity in humans. Adipocyte-specific ablation of mitochondrial carrier homolog 2 improves mitochondrial function and whole-body energy expenditure, independent of uncoupling protein 1. Furthermore, mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction, leading to enhanced energy expenditure in adipocytes/adipose tissue. Here we show mitochondrial carrier homolog 2 functions as a negative regulator of energy metabolism in adipocytes and represents a potential target for treating obesity and related metabolic disorders.

Date: 2025
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DOI: 10.1038/s41467-025-63880-7

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