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

Mitochondrial 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. Mitochondrial dynamics affect the thermogenic capacity of brown adipose tissue. Here, the authors show that TMEM135 regulates thermogenesis and energy homeostasis by mediating mitochondrial fission in brown adipocytes.

Automated summary

Mitochondrial morphology, regulated by fission and fusion, plays a crucial role in the thermogenic capacity of brown adipocytes. TMEM135 has been identified as a critical mediator in the regulation of mitochondrial fission and thermogenesis, providing a potential target for therapeutic activation of brown adipose tissue.