Knockdown of TMEM160 leads to an increase in reactive oxygen species generation and the induction of the mitochondrial unfolded protein response

Abstract

Transmembrane protein 160 (TMEM160) was recently reported to be localized to the mitochondrial inner membrane, but mitochondrial function was noted to be unaffected by loss of TMEM160. In contrast to these previously published findings, we report here that the absence of TMEM160 influences intracellular responses. After confirming that TMEM160 is localized in the inner mitochondrial membrane, we knocked down TMEM160 in human cultured cells and analyzed the changes in cellular responses. TMEM160 depletion led to an upregulation of the mitochondrial chaperone HSPD1, suggesting that depletion induced the mitochondrial unfolded protein response (UPR mt ). Indeed, the expression of key transcription factors that induce the UPR mt (ATF4, ATF5, and DDIT3) was increased following TMEM160 depletion. Expression of the mitochondrial protein import-receptors TOMM22 and TOMM20 was also enhanced. In addition, we observed a significant increase in reactive oxygen species (ROS) generation following TMEM160 depletion. Glutathione S-transferases, which detoxify the products of oxidative stress, were also upregulated in TMEM160-depleted cells. Immunoblot analysis was performed to detect proteins modified by 4-hydroxynonenal (which is released after the peroxidation of lipids by ROS): the expression patterns of 4-hydroxynonenalmodified proteins were altered after TMEM160 depletion, suggesting that depletion enhanced degradation of these proteins. HSPD1, TOMM22, ATF4, ATF5, and DDIT3 remained upregulated after ROS was scavenged by N-acetylcysteine, suggesting that once the UPR mt is induced by TMEM160 depletion, it is not suppressed by the subsequent detoxification of ROS. These findings suggest that TMEM160 may suppress ROS generation and stabilize mitochondrial protein(s).

Bioorthogonal photocatalytic proximity labeling in primary living samples

“…13). A recent study 34 published during our research period has concurrently confirmed human TMEM160 to be mitochondrial, further validating the efficacy of CAT-S-guided mitochondrial discovery. These findings indicated the in situ profiling by CAT-S could also shed light on the hidden members of the mitochondrial proteome.…”

Bioinformatic analysis and machine learning to identify the diagnostic biomarkers and immune infiltration in adenomyosis

“…Mitochondria are organelles of the cell respiratory system and provide ATP and ROS. Many studies have indicated that downregulation of TOMM20 could represent mitochondrial dysfunction and is often accompanied with increased oxidative stress ( Brown et al, 2019 ; Nhu et al, 2021 ; Yamashita et al, 2022 ). Oxidative stress is associated with various gynecological diseases, including adenomyosis ( de Carvalho et al, 2013 ).…”

The transmembrane proteins (TMEM) and their role in cell proliferation, migration, invasion, and epithelial-mesenchymal transition in cancer

“…TMEM proteins are located in different biological membranes. For example, TMEM180 is in the plasma membrane ( 11 ), TMEM165 is in the late Golgi (trans) ( 12 ), and endoplasmic reticulum (ER) ( 13 ), TMEM74 and TMEM9 in the lysosome membrane ( 14 – 16 ), TMEM106A ( 17 ) and TMEM160 in the mitochondrial membrane ( 18 , 19 ), and TMEM48 in the nuclear membrane ( 20 ). For some TMEM proteins, their localization has been demonstrated experimentally for others, it has been predicted by bioinformatics tools ( Table 1 ).…”