TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis

Author:

Hu Donghua,Tan Min,Lu Dongliang,Kleiboeker BrianORCID,Liu Xuejing,Park Hongsuk,Kravitz Alexxai V.ORCID,Shoghi Kooresh I.,Tseng Yu-HuaORCID,Razani BabakORCID,Ikeda AkihiroORCID,Lodhi Irfan J.ORCID

Abstract

AbstractMitochondrial morphology, which is controlled by mitochondrial fission and fusion, is an important regulator of the thermogenic capacity of brown adipocytes. Adipose-specific peroxisome deficiency impairs thermogenesis by inhibiting cold-induced mitochondrial fission due to decreased mitochondrial membrane content of the peroxisome-derived lipids called plasmalogens. Here, we identify TMEM135 as a critical mediator of the peroxisomal regulation of mitochondrial fission and thermogenesis. Adipose-specific TMEM135 knockout in mice blocks mitochondrial fission, impairs thermogenesis, and increases diet-induced obesity and insulin resistance. Conversely, TMEM135 overexpression promotes mitochondrial division, counteracts obesity and insulin resistance, and rescues thermogenesis in peroxisome-deficient mice. Mechanistically, thermogenic stimuli promote association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Together, these results reveal a previously unrecognized inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT.

Funder

U.S. Department of Health & Human Services | NIH | Office of Extramural Research, National Institutes of Health

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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