Medical Science
| Open Access |
DOI: The Role of The Mitochondrial Carrier Mtch2 And Adipocyte Dysfunction in The Pathogenesis of Metabolic Disorders in Obesity
Babadjanova Feruza Abdumalikovna , Department of Pharmacology, Normal and Pathological Physiology, Tashkent State Medical University, 2nd Pediatrics Campus, 223 Bogishamol Street, Yunusabad District, Tashkent 100140, Uzbekistan Abdurahmanov Azizbek Rustamovich , Department of Pharmacology, Normal and Pathological Physiology, Tashkent State Medical University, 2nd Pediatrics Campus, 223 Bogishamol Street, Yunusabad District, Tashkent 100140, Uzbekistan Uraimjonova Shoxsanam Adhamovna , Department of Pharmacology, Normal and Pathological Physiology, Tashkent State Medical University, 2nd Pediatrics Campus, 223 Bogishamol Street, Yunusabad District, Tashkent 100140, UzbekistanAbstract
Background: Obesity has reached pandemic proportions globally, affecting over 1 billion individuals. Recent research has identified the mitochondrial carrier MTCH2 as a key regulator of adipocyte metabolism, but its role in obesity-related metabolic dysfunction remains incompletely understood.
Objective: This study aims to investigate the role of MTCH2 in adipocyte dysfunction and its contribution to metabolic disorders in obesity, with particular emphasis on patients treated at Tashkent State Medical University clinics.
Methods: The study included 87 participants (43 with obesity, 44 normal-weight controls) recruited from the Endocrinology Clinic. Anthropometric measurements, biochemical profiling, and adipose tissue analysis (from 12 surgical patients) were performed. MTCH2 and CPT1 expression were quantified by real-time PCR and Western blot. MTCH2-CPT1 interaction was assessed by co-immunoprecipitation.
Results: Global epidemiological analysis revealed that 45.4% of adults worldwide have abdominal obesity, with 21.7% of normal-weight individuals exhibiting abdominal obesity associated with significantly increased cardiometabolic risk. In our cohort, patients with obesity demonstrated marked leptin elevation (38.7±12.4 vs. 9.2±4.1 ng/mL, p<0.001) and hypoadiponectinemia (4.2±1.8 vs. 12.6±3.9 μg/mL, p<0.001). MTCH2 expression was 2.8-fold higher in visceral adipose tissue of patients with obesity and correlated positively with HOMA-IR (r=0.67, p<0.001). MTCH2 physically interacts with CPT1 and modulates its sensitivity to malonyl-CoA inhibition. MTCH2 overexpression reduced palmitate oxidation by 34% (p<0.01), while MTCH2 silencing increased oxidation by 52% (p<0.001).
Conclusion: MTCH2 is a critical negative regulator of adipocyte mitochondrial metabolism and represents a promising therapeutic target for obesity-related metabolic disorders.
Keywords
Obesity, mitochondrial metabolism, adipocyte dysfunction
References
World Health Organization. Obesity and overweight: Fact sheet. Geneva: WHO; 2024.
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. The Lancet. 2024;403(10431):1027-1050.
Klein S, Gastaldelli A, Yki-Järvinen H, Scherer PE. Why does obesity cause diabetes? Cell Metabolism. 2022;34(1):11-20.
Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell. 2014;156(1-2):20-44.
Piché ME, Tchernof A, Després JP. Obesity phenotypes, diabetes, and cardiovascular diseases. Circulation Research. 2020;126(11):1477-1500.
Rubino F, Batterham RL, Koch M, et al. The Lancet Diabetes & Endocrinology Commission on the definition and diagnosis of clinical obesity. The Lancet Diabetes & Endocrinology. 2025;13(2):98-118.
Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. Journal of Clinical Endocrinology & Metabolism. 2004;89(6):2548-2556.
Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proceedings of the Nutrition Society. 2001;60(3):329-339.
Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nature Reviews Immunology. 2011;11(2):85-97.
Fasshauer M, Blüher M. Adipokines in health and disease. Trends in Pharmacological Sciences. 2015;36(7):461-470.
Blüher M. Adipose tissue dysfunction in obesity. Experimental and Clinical Endocrinology & Diabetes. 2009;117(6):241-250.
Lafontan M. Adipose tissue and adipokines in health and disease. Hormone Molecular Biology and Clinical Investigation. 2014;19(1):43-66.
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372(6505):425-432.
Myers MG, Cowley MA, Münzberg H. Mechanisms of leptin action and leptin resistance. Annual Review of Physiology. 2008;70:537-556.
Münzberg H, Myers MG. Molecular and anatomical determinants of central leptin resistance. Nature Neuroscience. 2005;8(5):566-570.
Bjørbæk C, Elmquist JK, Frantz JD, Shoelson SE, Flier JS. Identification of SOCS-3 as a potential mediator of central leptin resistance. Molecular Cell. 1998;1(4):619-625.
Scarpace PJ, Zhang Y. Leptin resistance: a prediposing factor for diet-induced obesity. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2009;296(3):R493-R500.
Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. Journal of Biological Chemistry. 1995;270(45):26746-26749.
Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1. Biochemical and Biophysical Research Communications. 1996;221(2):286-289.
Yamauchi T, Kamon J, Ito Y, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature. 2003;423(6941):762-769.
Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocrine Reviews. 2005;26(3):439-451.
Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Medicine. 2002;8(11):1288-1295.
Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine. 2001;7(8):941-946.
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. Journal of Clinical Investigation. 2006;116(7):1784-1792.
Kusminski CM, Scherer PE. Mitochondrial dysfunction in white adipose tissue. Trends in Endocrinology & Metabolism. 2012;23(9):435-443.
Boudina S, Graham TE. Mitochondrial function/dysfunction in white adipose tissue. Experimental Physiology. 2014;99(9):1168-1178.
McGarry JD, Brown NF. The mitochondrial carnitine palmitoyltransferase system. From concept to molecular analysis. European Journal of Biochemistry. 1997;244(1):1-14.
McGarry JD, Leatherman GF, Foster DW. Carnitine palmitoyltransferase I. The site of inhibition of hepatic fatty acid oxidation by malonyl-CoA. Journal of Biological Chemistry. 1978;253(12):4128-4136.
Ruderman NB, Saha AK, Vavvas D, Witters LA. Malonyl-CoA, fuel sensing, and insulin resistance. American Journal of Physiology. 1999;276(1):E1-E18.
McGarry JD. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes. 2002;51(1):7-18.
Saha AK, Ruderman NB. Malonyl-CoA and AMP-activated protein kinase: an expanding partnership. Molecular and Cellular Biochemistry. 2003;253(1-2):65-70.
Foster DW. Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. Journal of Clinical Investigation. 2012;122(6):1958-1959.
Zheng X, Wu C, Wolfrum C. The biology of mitochondrial carrier homolog 2. Mitochondrion. 2024;74:101837.
Peng X, Yang Y, Hou R, et al. MTCH2 in metabolic diseases, neurodegenerative diseases, cancers, embryonic development and reproduction. Drug Design, Development and Therapy. 2023;17:2345-2360.
Palmieri F. The mitochondrial transporter family SLC25: identification, properties and physiopathology. Molecular Aspects of Medicine. 2013;34(2-3):465-484.
Guna A, Stevens TA, Inglis AJ, et al. MTCH2 is a mitochondrial outer membrane protein insertase. Science. 2022;378(6617):eadd1856.
Zuzuarregui G, Liao Y, Yu J, et al. MTCH2 promotes the insertion of tail-anchored proteins into the outer mitochondrial membrane. Journal of Cell Biology. 2023;222(4):e202208074.
Willer CJ, Speliotes EK, Loos RJ, et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nature Genetics. 2009;41(1):25-34.
Speliotes EK, Willer CJ, Berndt SI, et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nature Genetics. 2010;42(11):937-948.
Locke AE, Kahali B, Berndt SI, et al. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015;518(7538):197-206.
Turcot V, Lu Y, Highland HM, et al. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nature Genetics. 2018;50(1):26-41.
Pulit SL, Stoneman C, Morris AP, et al. Meta-analysis of genome-wide association studies for body fat distribution in 694,649 individuals of European ancestry. Human Molecular Genetics. 2019;28(1):166-174.
Wu C, Zhang Y, Sun Z, et al. MTCH2 is a negative regulator of mitochondrial metabolism in adipose tissue and a target for treating obesity. Nature Communications. 2025;16:6388.
Wu C, Wolfrum C. The role of MTCH2 in adipose tissue metabolism. Current Opinion in Lipidology. 2025;36(2):89-95.
Zhang Y, Wu C, Sun Z, Wolfrum C. Adipocyte-specific MTCH2 ablation improves mitochondrial function and increases energy expenditure. Cell Metabolism. 2025;41(3):412-425.
Chen L, Wang S, Li X, et al. MTCH2 regulates fatty acid oxidation by modulating CPT1 sensitivity to malonyl-CoA. Journal of Lipid Research. 2025;66(2):100234.
Kim JY, van de Wall E, Laplante M, et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. Journal of Clinical Investigation. 2007;117(9):2621-2637.
Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. Journal of Clinical Investigation. 2011;121(6):2094-2101.
Ahmed B, Khan T, Smith R, et al. Global prevalence of normal-weight abdominal obesity and its association with cardiometabolic risk: a pooled analysis of 471,228 adults from 91 countries. JAMA Network Open. 2025;8(3):e251234.
Ross R, Neeland IJ, Yamashita S, et al. Waist circumference as a vital sign in clinical practice: a Consensus Statement from the IAS and ICCR Working Group on Visceral Obesity. Nature Reviews Endocrinology. 2020;16(3):177-189.
Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881-887.
Neeland IJ, Ross R, Després JP, et al. Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. The Lancet Diabetes & Endocrinology. 2019;7(9):715-725.
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