Poster only 3rd Metabolic Diseases; Breakthrough Discoveries in Diabetes & Obesity 2022

LETMD1 is a mitochondrial inner membrane protein critical for brown fat thermogenesis (#131)

Shihuan Kuang 1 , Madigan Snyder 1 , Feng Yue 1 2 , Pengpeng Bi 3
  1. Purdue University, West Lafayette, IN, United States
  2. University of Florida, Gainesville, FL, USA
  3. University of Georgia, Athens, Georgia, USA

LETMD1 has been recognized as an oncoprotein elevated in many cancer types, but its physiological function was unclear. Recent work has begun to elucidate a pro-inflammatory role of LETMD1 in macrophages beyond cancer cells (PMID: 31980577), but how LETMD1 functions in mitochondria enriched cells and tissues was only reported very recently by us and other. We show that LETMD1 is specifically enriched in the mitochondria of brown adipose tissue (BAT). We further demonstrate that LETMD1 is a mitochondrial inner membrane protein in BAT, as opposed to the reported outer membrane localization in human embryonic kidney cells (PMID: 18045496). Using a novel Letmd1 knockout (Letmd1KO) mouse model, we show that the Letmd1KO mice were born normally and have normal morphology and body weight, but they were unable to maintain body temperature in response to acute cold exposure in the absence of food and became lethally hypothermic within 4 h.  Although the Letmd1KO mice can can maintain body temperature during chronic cold exposure 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 suggest that the Letmd1KO mice use UCP1-independent thermogenic pathway to maintain body temperature. During postnatal expansion of the brown adipose tissue (BAT), the Letmd1KO brown adipocytes progressively lost their multilocular characteristics and diminished their mitochondrial abundance, DNA copy number, cristae structure, and thermogenic gene expression. As consequence, the Letmd1KO brown adipocytes exhibited elevated reactive oxidative stress. These results demonstrate that LETMD1 is essential for mitochondrial structure and function, and thermogenesis of brown adipocytes. Our ongoing work is elucidating if and how LETMD mediate mitochondrial function and thermogenesis in brown adipocytes in a cell autonomous manner.

Results partially published in Snyder MM, et al., FASEB J. 2021 Nov;35(11):e21965. doi: 10.1096/fj.202100597R.