Tmem135, a transmembrane protein, is thought to regulate the balance between mitochondrial fusion and fission, and plays roles in lipid droplet formation/tethering, fatty acid metabolism, and peroxisomal function [3]. It is also involved in pathways related to energy homeostasis, osteogenesis-adipogenesis equilibrium, and primary ciliogenesis [1,2,4].

In adipose-specific Tmem135 knockout mice, mitochondrial fission is blocked, thermogenesis is impaired, and diet-induced obesity and insulin resistance increase, while overexpression promotes mitochondrial division and counteracts these phenotypes, revealing its role in regulating brown fat mitochondrial fission and energy homeostasis [1]. Tmem135 knockout mice also show an osteoporotic phenotype due to impaired mitochondrial fission and disrupted energy metabolism during osteogenesis, indicating its importance in maintaining the equilibrium of osteogenesis and adipogenesis [2]. In addition, a mutation in Tmem135 in mice causes progressive sensorineural hearing loss, with loss of outer hair cells and spiral ganglion neurons in the cochlea [5,8]. TMEM135 deficiency improves hepatic steatosis by suppressing CD36 in a SIRT1-dependent manner [6]. Overexpression and mutation of Tmem135 lead to contrasting retinal pigmented epithelium (RPE) abnormalities in mice, suggesting proper regulation of mitochondrial homeostasis by TMEM135 is critical for RPE health [7].

In summary, Tmem135 is crucial for multiple biological functions mainly through regulating mitochondrial dynamics. Studies using Tmem135 KO mouse models have revealed its significance in diseases such as obesity, insulin resistance, osteoporosis, hearing loss, hepatic steatosis, and retinal pathologies, providing insights into the underlying mechanisms and potential therapeutic targets for these conditions.