ESPEYB21 11. Obesity and Weight Regulation Adipocyte Dysfunction and Obesity Related Comorbidities (4 abstracts)
11.14. Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation
Xia W , Veeragandham P , Cao Y , Yayun Xu Y , Rhyne TE , Qian J , Chao-Wei Hung , CHZhao P , Jones Y , Hui Gao H , Liddle C , Yu RT , Downes M , Evans RM , Rydén M , Wabitsch M , Wang Z , Hakozaki H , Schöneberg J , Reilly SM , Huang J & Saltiel AR
Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, San Diego.
asaltiel@health.ucsd.edu
Nat Metab. 2024; 6(2): 273-289. doi:10.1038/s42255-024-00978-. https://pubmed.ncbi.nlm.nih.gov/38286821/
Brief Summary: This study shows that obesity induces mitochondrial fragmentation and reduces oxidative capacity in white adipocytes through the activation of the small GTPase RalA. Targeted deletion of RalA in these cells prevents mitochondrial fragmentation, improves energy expenditure, and protects against obesity-induced metabolic dysfunctions, highlighting the critical role of RalA in obesity-related mitochondrial and metabolic abnormalities.
Previous research established that mitochondrial dysfunction is a hallmark of obesity, contributing to insulin resistance and other metabolic disorders1. This study extends that knowledge by elucidating a specific molecular mechanism involving RalA activation, which leads to mitochondrial fragmentation in white adipocytes. RalA, a member of the Ras superfamily of GTPases, is involved in various cellular processes including proliferation and cell survival in cancer context2. Its specific role in adipocyte metabolism and mitochondrial dynamics was unclear. Here, targeted deletion of RalA in white adipocytes prevented mitochondrial fragmentation, enhanced oxidative capacity, and increased energy expenditure via Drp1 phosphorylation. Further, RalA knockout protected mice on high-fat diet from development of insulin resistance. These findings have broader implications for metabolic research beyond obesity. The identification of a new regulatory axis involving RalA and Drp1 in mitochondrial dynamics may be relevant to other metabolic tissues and conditions. This could lead to a deeper understanding of mitochondrial biology and its role in other metabolic diseases.
References: 1. Chen W, Zhao H, Li Y. Mitochondrial dynamics in health and disease: mechanisms and potential targets. Signal Transduct. Target. Ther. 2023; 8. doi:10.1038/s41392-023-01547-9.2. Yan C, Theodorescu D. RAL GTpases: Biology and potential as therapeutic targets in cancer. Pharmacol Rev 2018; 70: 1–11.
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