Transmembrane protein 135 regulates lipid homeostasis through its role in peroxisomal DHA metabolism

Abstract

Transmembrane protein 135 (TMEM135) is thought to participate in the cellular response to increased intracellular lipids yet no defined molecular function for TMEM135 in lipid metabolism has been identified. In this study, we performed a lipid analysis of tissues from Tmem135 mutant mice and found striking reductions of docosahexaenoic acid (DHA) across all Tmem135 mutant tissues, indicating a role of TMEM135 in the production of DHA. Since all enzymes required for DHA synthesis remain intact in Tmem135 mutant mice, we hypothesized that TMEM135 is involved in the export of DHA from peroxisomes. The Tmem135 mutation likely leads to the retention of DHA in peroxisomes, causing DHA to be degraded within peroxisomes by their beta-oxidation machinery. This may lead to generation or alteration of ligands required for the activation of peroxisome proliferator-activated receptor a (PPARa) signaling, which in turn could result in increased peroxisomal number and beta-oxidation enzymes observed in Tmem135 mutant mice. We confirmed this effect of PPARa signaling by detecting decreased peroxisomes and their proteins upon genetic ablation of Ppara in Tmem135 mutant mice. Using Tmem135 mutant mice, we also validated the protective effect of increased peroxisomes and peroxisomal beta-oxidation on the metabolic disease phenotypes of leptin mutant mice which has been observed in previous studies. Thus, we conclude that TMEM135 has a role in lipid homeostasis through its function in peroxisomes.

The peroxisome: an update on mysteries 3.0

“…Furthermore, mice overexpressing the dual peroxisomal/mitochondrial protein TMEM135 (Fig. 1 ), which negatively regulates peroxisome abundance (Landowski et al 2023 ), have a reduced redox ratio in the heart and display mild hypertrophy due to collagen accumulation (Lewis et al 2018 ), though the contribution of peroxisomes versus mitochondria to this phenotype is unknown. Conversely, FAR1, which is involved in ether phospholipid synthesis at peroxisomes (Fig.…”

Glutathione and peroxisome redox homeostasis

“…Despite the scarcity of transmembrane proteins in peroxisomes (reviewed in Ref. [ 69 ]), mice or mammalian cells lacking one of these proteins or possessing a severe mutation in the corresponding gene do not display signs of a general peroxisome deficiency [ 69 , [78] , [79] , [80] , [81] , [82] , [83] , [84] , [85] , [86] ]. One possibility to explain these findings is that other peroxisomal antioxidant defenses ( e.g.…”

A Mutation inTmem135Causes Progressive Sensorineural Hearing Loss

“…TMEM135 is thought to have a role in lipid metabolism and homeostasis: in C. elegans, deletion of tmem135 causes a reduction in fat stores and decreased longevity, while C. elegans transgenic animals overexpressing TMEM-135 exhibit increased longevity upon exposure to cold stress (Exil et al, 2010). In mice, a point mutation in Tmem135 impairs lipid metabolism in the eye (Landowski et al, 2022) and regulates the docosahexaenoic acid (DHA) metabolism with the liver, retina, heart, and plasma (Landowski et al, 2023). In human cell lines, TMEM135 is a potential candidate for regulating intracellular cholesterol transport through lysosome-peroxisome membrane contacts (Chu et al, 2015), and regulates primary ciliogenesis through the modulation of intracellular cholesterol distribution (Maharjan et al, 2020).…”