Identification of Letmd1 as a novel regulator of mitochondrial OXPHOS complex in brown adipose tissue

Abstract

Mitochondria play diverse roles in metabolism, development, and disease. To carry out these diverse roles, mitochondrial dynamics, ultrastructure, proteomes and their regulation differ depending on tissue and cell types. Brown adipose tissue mitochondria carry out their unique function of generating heat through uncoupled respiration. The key to thermogenic mitochondria is the presence of Uncoupling protein 1 (Ucp1) which is expressed at high levels specifically in the brown adipocyte. Ucp1 facilitates proton leakage in the inner membrane of mitochondria to mediate heat generation in the brown adipocyte. However, other mitochondrial factors may be required for optimal thermogenic capacity of brown adipocyte mitochondria. Several mitochondrial proteins are suggested as cold-inducible factors in the brown adipose tissue, but most of the candidates are uncharacterized. Here we show that LETM1 domain-containing protein 1 (Letmd1) is required for cold-stimulated respiration of brown adipose tissue. Letmd1 knockout mice have impaired OXPHOS complex formation followed by dysfunction of heat generation during cold exposure. Biotin-phenol proximity labeling technique reveals that Letmd1 is a mitochondrial matrix protein, and mitochondrial ultrastructure of Letmd1-deficient brown adipocyte is highly disorganized. Mechanistically, Letmd1 contributes to the formation of oxidative phosphorylation (OXPHOS) complex through interaction with the mitochondrial ribosomal protein L39 (Mrpl39) at the inner membrane of the mitochondria. Overexpression of Letmd1 enhanced oxygen consumption rate in white adipocytes. These findings suggest that Letmd1 has a key role between OXPHOS function with cold-stimulated thermogenesis. This study will contribute to a more complete understanding of mitochondrial biology to overcome metabolic diseases.