LETMD1 is required for mitochondrial structure and thermogenic function of brown adipocytes

Abstract

Obesity and metabolic disorders caused by energy surplus pose an increasing concern within the global population. Brown adipose tissue (BAT) dissipates energy through mitochondrial non-shivering thermogenesis, thus representing a powerful agent against obesity. Here we explore the novel role of a mitochondrial outer membrane protein, LETM1-domain containing 1 (LETMD1), in BAT. We generated a knockout (Letmd1 KO ) mouse model and analyzed BAT morphology, function and gene expression under various physiological conditions. While the Letmd1 KO mice are born normally and have normal morphology and body weight, they lose multilocular brown adipocytes completely and have diminished mitochondrial abundance, DNA copy number, cristae structure, and thermogenic gene expression in the intrascapular BAT, associated with elevated reactive oxidative stress. In consequence, the Letmd1 KO mice fail to maintain body temperature in response to acute cold exposure without food and become hypothermic within 4 h. Although the cold-exposed Letmd1 KO mice can maintain body temperature in the presence of food, they cannot upregulate expression of uncoupling protein 1 (UCP1) and convert white to beige adipocytes, nor can they respond to adrenergic stimulation. These results demonstrate that LETMD1 is essential for mitochondrial structure and function, and thermogenesis of brown adipocytes.

Obesity III: Obesogen assays: Limitations, strengths, and new directions

“…Specifically, the ThermoMouse model measures thermogenesis via luciferase activity linked to levels of UCP1 expression in BAT following environmental stimuli (e.g., decreased temperatures) [238], which has also been adapted as an in vitro assay to screen small molecules for luciferase activity [238]. This assay has supported screening of potential drug targets that promote UCP1, and which could provide a foundation for future BAT-mediated drug therapies that could induce thermogenesis and energy expenditure [239][240][241][242][243].…”

Identification and experimental validation of mitochondria-related genes biomarkers associated with immune infiltration for sepsis

“…Protein 1 of the LETM1 domain (LETMD1), also known as HCCR-1, is a mitochondrial protein. Limited studies have shown that LETMD1 is essential for the mitochondrial structure and thermogenic function of brown fat cells ( 37 ). LETMD1 selectively regulates reactive oxygen generation and NF-κB activation in macrophages through MyD88, thus regulating phagocytosis and inflammatory response to lipopolysaccharide ( 38 ).…”

Mitochondrial matrix protein LETMD1 maintains thermogenic capacity of brown adipose tissue in male mice

“…For instance, Choi et al 46 demonstrated an interaction between LETMD1 and Brg1 in the nucleus, suggesting a potential link to transcriptional regulation of BAT thermogenesis. Snyder et al 47 demonstrated that LETMD1 is essential for BAT structure and OXPHOS expression, even under thermoneutral conditions. Song et al 48 observed perturbations in mitochondrial calcium homeostasis in brown adipocytes lacking LETMD1, while Xiao et al 49 reported the localization of LETMD1 to the mitochondrial inner membrane.…”