MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes
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.
Authors
- Adhideb Ghosh (ORCID: https://orcid.org/0000-0002-5160-4571)
- Ilenia Severi (ORCID: https://orcid.org/0000-0002-3985-1131)
- Saverio Cinti (ORCID: https://orcid.org/0000-0003-0362-5017)
- Sarantos Kostidis (ORCID: https://orcid.org/0000-0002-2040-2563)
- Jonatan R. Ruiz (ORCID: https://orcid.org/0000-0002-7548-7138)
- Lianggong Ding (ORCID: https://orcid.org/0000-0001-9385-7799)
- Christian Wolfrum (ORCID: https://orcid.org/0000-0002-3862-6805)
- Martin Giera (ORCID: https://orcid.org/0000-0003-1684-1894)
- Antonio Giordano (ORCID: https://orcid.org/0000-0003-1401-5855)
- Falko Noé (ORCID: https://orcid.org/0009-0002-3360-5455)
- Radhika Khandelwal (ORCID: https://orcid.org/0000-0002-5323-9846)
- Lucia Balážová (ORCID: https://orcid.org/0000-0001-6765-7486)
- Sandra Kleiner
- Juan M. A. Alcántara (ORCID: https://orcid.org/0000-0002-8842-374X)
- Sabita Chourasia (ORCID: https://orcid.org/0009-0000-9282-5170)
- Fen Long
- Tina Dahlby (ORCID: https://orcid.org/0000-0003-1656-0814)
- Anton Pekcec (ORCID: https://orcid.org/0000-0001-9045-4740)
- Anand K. Sharma (ORCID: https://orcid.org/0000-0001-7532-5983)
- Atan Gross (ORCID: https://orcid.org/0000-0002-5636-7296)
- Bart Deplancke (ORCID: https://orcid.org/0000-0001-9935-843X)
- Georgia Colleluori (ORCID: https://orcid.org/0000-0002-4908-9873)
- Miroslav Baláž (ORCID: https://orcid.org/0000-0002-5740-4896)
- Vincent Gardeux (ORCID: https://orcid.org/0000-0001-8954-2161)
- Heike Neubauer (ORCID: https://orcid.org/0000-0001-8470-968X)
- Matthias Blüher (ORCID: https://orcid.org/0000-0003-0208-2065)
- Tongtong Wang (ORCID: https://orcid.org/0000-0001-6745-1752)
- Chunyan Wu (ORCID: https://orcid.org/0000-0002-1511-4903)
- Bradford S. Hamilton
- Laith Abu-Nawwas
Institutions
- Marche Polytechnic University (IT)
- SIB Swiss Institute of Bioinformatics (CH)
- Boehringer Ingelheim (Germany) (DE)
- Nanyang Technological University (SG)
- Universidad de Granada (ES)
- Leiden University Medical Center (NL)
- Helmholtz Zentrum München (DE)
- ETH Zurich (CH)
- Netherlands Metabolomics Centre (NL)
- Centro de Investigación Biomédica en Red (ES)
- Biomedical Research Center of the Slovak Academy of Sciences (SK)
- École Polytechnique Fédérale de Lausanne (CH)
- University of Almería (ES)
- Weizmann Institute of Science (IL)
- Comenius University Bratislava (SK)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1038/s41467-025-63880-7
- Citations
- 2
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- European Commission
- Universiteit Leiden
- Eidgenössische Technische Hochschule Zürich
- Leids Universitair Medisch Centrum
- Agentúra na Podporu Výskumu a Vývoja
- Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
- Agencia Estatal de Investigación
- European Social Fund