Mitochondrial dynamics and the control of adipose tissue thermogenesis

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Project Summary Therapeutic expansion or activation of brown adipose tissue (BAT) has a potential to be an effective treatment for obesity. BAT, as well as the closely-related beige fat, are characterized by their abundance of mitochondria, which are involved in thermogenesis through uncoupled respiration. In addition to the importance of mitochondrial functions, mitochondrial morphology plays a critical role in thermogenesis. Mitochondria are highly dynamic organelles that continuously undergo cycles of fission and fusion. Adrenergic stimulation-induced mitochondrial fission in BAT promotes uncoupled respiration and thermogenesis. Like mitochondria, peroxisomes are enriched in BAT. Our recently published studies indicate that peroxisomes play a critical role in thermogenesis through their ability to regulate cold-induced mitochondrial fission. The defect in mitochondrial fission and thermogenesis in mice with adipose-specific knockout of the critical peroxisomal biogenesis factor Pex16 (Pex16-AKO) could be rescued by dietary supplementation of peroxisome-derived lipids called plasmalogens. This project seeks to understand the molecular mechanism of peroxisomal regulation of mitochondrial dynamics and thermogenesis. Our preliminary data suggest that norepinephrine stimulation, which activates mitochondrial fission, promotes recruitment of peroxisomes to mitochondria. To understand the role of peroxisomes in mitochondrial dynamics, we performed protein mass spectrometry on mitochondria isolated from BAT of Pex16-AKO and control mice. TMEM135, a peroxisomal and mitochondrial membrane protein, was identified as the most dramatically decreased protein in the knockout BAT mitochondria, with no change of its levels in whole tissue lysates, suggesting that the protein is mistargeted in the absence of peroxisomes. TMEM135 expression in BAT increases with cold exposure. Its knockdown in brown adipocytes results in tubular mitochondria, while the overexpression promotes mitochondrial fragmentation. We hypothesize that peroxisome- mitochondria membrane contacts regulate mitochondrial localization of TMEM135 in a plasmalogen-dependent manner and that TMEM135 mediates mitochondrial fission to promote thermogenesis. We propose three specific aims to test this hypothesis. The first aim will define the role of TMEM135 in mitochondrial dynamics and function in brown adipocytes. The second aim will determine if TMEM135 overexpression in mice promotes energy expenditure through increased BAT mitochondrial fission and if it rescues thermogenesis in Pex16-AKO mice. The last aim focuses on understanding the role of TMEM135 in mitochondrial dynamics, thermogenesis, adiposity, and metabolic homeostasis using mice with adipose-specific knockout of TMEM135. Overall, this project has the potential to identify a novel organelle interaction regulating mitochondrial division, characterized by recruitment of peroxisomes to mitochondria, perhaps leading to new potential targets for therapeutic activation of BAT.