Work

Abnormal mitochondrial structure and function in brown adipose tissue of SLC35A4-MP knockout mice

Year: 2025

Type: article

Abstract: Uncovering the role of upstream open reading frames (uORFs) challenges conventional views of one protein per messenger RNA and reveals the capacity of some uORFs to encode microproteins that contribute to cellular biology and physiology. This study explores the functional role of a recently identified mitochondrial microprotein, SLC35A4-MP, in the brown adipose tissue of mice. Our findings reveal dynamic regulation of SLC35A4-MP expression during primary brown adipocyte differentiation in vitro and during cold exposure or high-fat diet (HFD)-induced obesity in mice. Using a knockout mouse model, we show that loss of SLC35A4-MP disrupts mitochondrial lipid composition, decreasing cardiolipins and phosphatidylethanolamine in brown adipose tissue from HFD-fed mice. SLC35A4-MP deficiency also impairs mitochondrial activity, alters mitochondrial number and morphology, and promotes inflammation. Knockout mice accumulate acylcarnitines during cold exposure, indicating defective fatty acid oxidation. These findings reveal SLC35A4-MP as a previously unrecognized microprotein in regulating mitochondrial function and tissue lipid metabolism, adding to the growing list of functional endogenous microproteins.

Source: Science Advances

DOI: 10.1126/sciadv.ads7381

Authors: Andréa L. Rocha, Christian Schmedt, Guy Perkins, Antonio Pinto, Jolene K. Diedrich, Huanqi Shan, Kaja Plucińska, Eduardo Vieira de Souza, Joan M. Vaughan, Mark Foster, Srinath C. Sampath, Srihari C. Sampath, Paul Cohen, Mark H. Ellisman, Alan Saghatelian

Institutions: Salk Institute for Biological Studies, Genomics Institute of the Novartis Research Foundation, University of California San Diego, Rockefeller University

Language: English

Topic: Adipose Tissue and Metabolism

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,500

Funders: National Institutes of Health, University of California, San Diego, National Institute on Aging, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke

Awards: Scalable electron tomography for connectomics, The complex interaction between Alzheimer drivers and aging, Advancing Multi-Color EM via Direct Detector-enabled 4D-STEM, 3D Reconstruction and Analysis of Alzheimer's Patient Biopsy Samples to Map and Quantify Hallmarks of Pathogenesis and Vulnerability, FEI TITAN HALO 300kV INTERMEDIATE VOLTAGE ELECTRON MICROSCOPE, Circadian Structural Plasticity in Central Pacemakers, Cancer Center Support Grant (CCSG), Reversing Microglial Inflammarafts and Mitochondrial Dysfunction in Alzheimer's Disease, The Discovery of Human Peptide Encoding Genes, An Encyclopedia of the Adipose Tissue Secretome to Identify Mediators of Health and Disease, National Center for Microscopy and Imaging Research: A BRAIN Technology Integration and Dissemination Resource

OpenAlex ID: W4413817788

FWCI: 3.713

Cites: 80

Cited by: 7

Related to: 10