Deletion ofLetmd1leads to the disruption of mitochondrial function in brown adipose tissue

Human cervical cancer oncogene (HCCR-1), also named as LETMD1, is a LETM-domain containing outer mitochondrial membrane protein which plays an important role in the carcinogenesis of cancers. Surprisingly, we found that loss of Letmd1 in mice leads to multiply severe abnormities, such as the brown adipose tissue (BAT) whitening, disruption of thermogenesis, cold-induced death, diet-induced obesity, hyperglycinemia and insulin resistance. Mechanistically, deletion of Letmd1 in BAT causes the reduction of mitochondrial calcium ion, which in turn results in the suppressed fission of mitochondria, and ultimately leads to the depletion of Ucp1 -mediated BAT heat production. This study indicates that LETMD1 plays a crucial role in controlling BAT thermogenesis and energy homeostasis by regulating mitochondrial structures and functions, and also provides a novel insight for the clinical biomarker and therapeutical target of oncogene for the metabolic disorders. Highlights Letmd1 is an oncogene and also highly expressed in brown adipose tissue (BAT) of human and mice. Loss of Letmd1 leads to BAT whitening, diet-induced obesity, hyperglycemia and insulin resistant. Letmd1 knockout causes the disruption of thermogenesis and death at 4°C exposure. Deletion of Letmd1 results in mitochondrial calcium homeostasis disorders. Graphic abstract