Tmem160 contributes to the establishment of discrete nerve injury-induced pain behaviors in male mice

Segelcke, Daniel; Fischer, Hanna K.; Hütte, Meike; Dennerlein, Sven; Benseler, Fritz; Pogatzki-Zahn, Esther; Schmidt, Manuela

doi:10.1016/j.celrep.2021.110152

Cited by 18 publications

(28 citation statements)

References 89 publications

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“…These results indicate that TMEM160 resides in the mitochondrial inner membrane or matrix. Taken together, our results confirm previous findings showing that TMEM160 is a transmembrane protein of the mitochondrial inner membrane [1].…”

Section: Discussionsupporting

confidence: 92%

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

2022

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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).

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Section: Discussionsupporting

confidence: 92%

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

2022

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“…The two pain-models, surgical incision, and pathogen-induced inflammation, both led to peripheral and central sensitization and resulted in mechanical hypersensitivity as a prominent symptom. This is consistent with our recent reports ( Segelcke et al, 2021b; Segelcke et al, 2021a ), in which we compared both pain models in a multimodal behavioral test battery: heat- and mechanically evoked as well as non-evoked pain-related responses, and gait parameters did not differ 24h after induction in both models. This was also true for peripheral macroscopic parameters of the inflammatory response (edema and hind paw skin temperature ( Segelcke et al, 2021b ).…”

Section: Discussionsupporting

confidence: 92%

“…However, strong differences existed regarding the mechanisms to induce hypersensitivity in both pain states. The incision, a model for local tissue injury-based peripheral sensitization, mainly recruits immune cells and leads to enhance cytokine and proinflammatory mediator concentration locally ( Pogatzki-Zahn, 2017; Segelcke et al, 2021b; Segelcke et al, 2021a ). It causes inflammation that affects skin, muscles, and internal organs, but not the brain directly, although this has not been precisely investigated yet ( Ji et al, 2018; Matsuda et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Distinct Functional cerebral Hypersensitivity networks during incisional and inflammatory pain in rats

Kreitz¹,

Pradier

Amirmohseni

et al. 2023

Preprint

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Although the pathophysiology of pain has been investigated tremendously, there are still many open questions, especially with regard to specific pain entities and their pain-related symptoms. To increase the translational impact of (preclinical) animal pain neuroimaging studies, the use of disease-specific pain models, as well as relevant stimulus modalities, are critical. Yet, the challenges of identifying neuroimaging signatures at a pain entity- and modality-specific level are manifold. Therefore, we developed a comprehensive framework for brain network analysis in disease-specific pain models combining functional MRI with graph-theory and data classification by linear discriminant analysis. This enabled us to expand our knowledge of stimulus (mechanical vs. electrical) modality processing under incisional (INC) and pathogen-induced inflammatory (CFA) pain entities compared to acute pain conditions. In short, graph-theoretical analyses revealed distinct Network Signatures of Pain Hypersensitivity (NSPH) for INC and CFA, resulting in impaired discrimination of stimulus modalities in both pain models compared to control conditions (CTR). Such specific neuroimaging signatures are an important step toward identifying novel pain biomarkers for certain diseases and relevant outcomes to evaluate target engagement of novel therapeutic options, which ultimately can be translated to the clinic.

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“…This mismatch between preclinical research and clinical application critically contributes to a lack of efficient translational pain research and therefore needs to be bridged ( Mouraux et al, 2021 ). Novel behavioral assays that detect clinically relevant symptoms of different pain entities are vastly underrepresented, and only a few studies show a multimodal approach to examining pain-associated behaviors ( Du Percie Sert and Rice, 2014; Mouraux et al, 2021; Segelcke et al, 2021a ). This problem is also present in CIBP research ( Currie et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

“…This problem is also present in CIBP research ( Currie et al, 2013 ). In the past two decades, novel, video-based assays have been developed to address (1) functional aspects, such as pain-related changes in gait patterns ( Pitzer et al, 2016; Segelcke et al, 2021a ), (2) non-evoked pain- (NEP) related behavior ( Djouhri et al, 2006; Pogatzki-Zahn et al, 2021; Tappe-Theodor and Kuner, 2014 ) or (3) changes in rodent-specific complex behavior (e.g., resting, ambulatory, social, and pain-related behaviors) ( Tappe-Theodor et al, 2019 ). In this context, monitoring behavior in home cage settings seems promising to broaden behavioral studies and investigate the animals within their familiar environments.…”

Section: Introductionmentioning

confidence: 99%

Behavioural Voluntary and Social Bioassays Enabling Identification of Complex and Sex-Dependent Pain- (-Related) Phenotypes in Rats with Bone Cancer

Segelcke

Linnemann

Pradier

et al. 2022

Preprint

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Cancer-induced bone pain (CIBP) is a common and devastating symptom with limited treatment options in patients, significantly affecting their quality of life. To uncover the mechanisms underlying CIBP, using rodent models is the most common approach; however, the translation of results to the clinic may be hindered because the assessment of pain-related behavior is often based exclusively on reflexive-based methods, which are only partially indicative relevant pain in patients. In order to improve the accuracy and strength of the preclinical experimental model of CIBP in rodents, we used a battery of multimodal behavioral tests that were also aimed at identifying rodent-specific behavioral components by using a homecage monitoring assay (HCM). Rats of all sexes received an injection with either heat-deactivated (sham-group) or potent mammary gland carcinoma Walker 256 cells into the tibia. By integrating multimodal datasets, we assessed pain-related behavioral trajectories of CIBP-phenotype, including evoked and non-evoked based assays and HCM. Using principal component analysis (PCA), we discovered sex-specific differences in establishing the CIBP-phenotype, which occurred earlier (and different) in males. In addition, HCM phenotyping revealed the occurrence of sensory-affective states manifested by mechanical hypersensitivity in sham when housed with a tumor-bearing cagemate (CIBP) of the same sex. This multimodal battery allows an in-depth characterization of the CIBP-phenotype under social aspects in rats. The detailed, sex-specific, and rat-specific social phenotyping of CIBP enabled by PCA provides the basis for mechanism-driven studies to ensure robustness and generalisability of results and provide information for targeted drug development in the future.

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Tmem160 contributes to the establishment of discrete nerve injury-induced pain behaviors in male mice

Abstract: Highlights d Discrete nerve injury-induced pain behaviors are delayed in male Tmem160 KO mice d Tmem160 is dispensable for other pain entities and in female KO mice d Tmem160 deficiency dampens neuroimmune signaling and

Cited by 18 publications

References 89 publications

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

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

Distinct Functional cerebral Hypersensitivity networks during incisional and inflammatory pain in rats

Behavioural Voluntary and Social Bioassays Enabling Identification of Complex and Sex-Dependent Pain- (-Related) Phenotypes in Rats with Bone Cancer

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