更新于：2024-11-01

SMDT1

更新于：2024-11-01

基本信息

别名

C22orf32、DDDD、dJ186O1.1

+ [5]

简介

Essential regulatory subunit of the mitochondrial calcium uniporter complex (uniplex), a complex that mediates calcium uptake into mitochondria (PubMed:24231807, PubMed:26774479, PubMed:27099988). Required to bridge the calcium-sensing proteins MICU1 and MICU2 with the calcium-conducting subunit MCU (PubMed:24231807). Plays a central role in regulating the uniplex complex response to intracellular calcium signaling (PubMed:27099988). Acts by mediating activation of MCU and retention of MICU1 to the MCU pore, in order to ensure tight regulation of the uniplex complex and appropriate responses to intracellular calcium signaling (PubMed:27099988).

关联

项与 SMDT1 相关的药物

NAV-205

靶点

SMDT1

作用机制

SMDT1 inhibitors

在研机构

Navrogen, Inc.初创企业

原研机构

Navrogen, Inc.初创企业

在研适应症

实体瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 SMDT1 相关的临床结果

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100 项与 SMDT1 相关的转化医学

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0 项与 SMDT1 相关的专利（医药）

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323

项与 SMDT1 相关的文献（医药）

2024-10-24·The Journal of Physical Chemistry B

Enhancing Spectrometer Performance with Unsupervised Machine Learning

Article

作者: Hu, Ziling ; Harding, Benjamin D. ; Henzler-Wildman, Katherine A. ; Delaglio, Frank ; Hiett, Ashley ; Rienstra, Chad M.

Solid-state NMR spectroscopy (SSNMR) is a powerful technique to probe structural and dynamic properties of biomolecules at an atomic level. Modern SSNMR methods employ multidimensional pulse sequences requiring data collection over a period of days to weeks. Variations in signal intensity or frequency due to environmental fluctuation introduce artifacts into the spectra. Therefore, it is critical to actively monitor instrumentation subject to fluctuations. Here, we demonstrate a method rooted in the unsupervised machine learning algorithm principal component analysis (PCA) to evaluate the impact of environmental parameters that affect sensitivity, resolution and peak positions (chemical shifts) in multidimensional SSNMR protein spectra. PCA loading spectra illustrate the unique features associated with each drifting parameter, while the PCA scores quantify the magnitude of parameter drift. This is demonstrated both for double (HC) and triple resonance (HCN) experiments. Furthermore, we apply this methodology to identify magnetic field B₀ drift, and leverage PCA to "denoise" multidimensional SSNMR spectra of the membrane protein, EmrE, using several spectra collected over several days. Finally, we utilize PCA to identify changes in B₁ (CP and decoupling) and B₀ fields in a manner that we envision could be automated in the future. Overall, these approaches enable improved objectivity in monitoring NMR spectrometers, and are also applicable to other forms of spectroscopy.

2024-10-24·Journal of Bacteriology

Substrate dependence of transport coupling and phenotype of a small multidrug resistance transporter in Pseudomonas aeruginosa

Article

作者: Wegrzynowicz, Andrea K. ; McLean, Maxwell S. ; Demas, Sydnye P. ; Peters, Jason M. ; Henzler-Wildman, Katherine A. ; Heelan, William J.

ABSTRACT Small multidrug resistance (SMR) transporters are key players in the defense of multidrug-resistant pathogens to toxins and other homeostasis-perturbing compounds. However, recent evidence demonstrates that EmrE, an SMR from Escherichia coli and a model for understanding transport, can also induce susceptibility to some compounds by drug-gated proton leak. This runs down the ∆pH component of the proton-motive force (PMF), reducing the viability of the affected bacteria. Proton leak may provide an unexplored drug target distinct from the targets of most known antibiotics. Activating proton leak requires an SMR to be merely present, rather than be the primary resistance mechanism, and dissipates the energy source for many other efflux pumps. PAsmr, an EmrE homolog from Pseudomonas aeruginosa , transports many EmrE substrates in cells and purified systems. We hypothesized that PAsmr, like EmrE, may confer susceptibility to some compounds via drug-gated proton leak. Growth assays of E. coli expressing PAsmr displayed substrate-dependent resistance and susceptibility phenotypes, and in vitro solid-supported membrane electrophysiology experiments revealed that PAsmr performs both antiport and substrate-gated proton uniport, demonstrating the same functional promiscuity observed in EmrE. Growth assays of P. aeruginosa strain PA14 demonstrated that PAsmr contributes resistance to some antimicrobial compounds, but no growth defect is observed with susceptibility substrates, suggesting P. aeruginosa can compensate for the proton leak occurring through PAsmr. These phenotypic differences between P. aeruginosa and E. coli advance our understanding of the underlying resistance mechanisms in P. aeruginosa and prompt further investigation into the role that SMRs play in antibiotic resistance in pathogens. IMPORTANCE Small multidrug resistance (SMR) transporters are a class of efflux pumps found in many pathogens, although their contributions to antibiotic resistance are not fully understood. We hypothesize that these transporters may confer not only resistance but also susceptibility, by dissipating the proton-motive force. This means to use an SMR transporter as a target; it merely needs to be present (as opposed to being the primary resistance mechanism). Here, we test this hypothesis with an SMR transporter found in Pseudomonas aeruginosa and find that it can perform both antiport (conferring resistance) and substrate-gated proton leak. Proton leak is detrimental to growth in Escherichia coli but not P. aeruginosa , suggesting that P. aeruginosa responds differently to or can altogether prevent ∆pH dissipation.

2024-10-01·Otology & Neurotology

Mendelian Randomization Study Reveals a Predicted Relationship between Sensorineural Hearing Loss and Mitochondrial Proteins

Article

作者: Wu, Linrong ; Yan, Jiangyu ; Pan, Fangfang ; Lv, Yuan ; Gao, Weibo ; Zheng, Mengmeng ; Jiang, Feng

BackgroundMitochondrial proteins assume a pivotal role in the onset and progression of diverse diseases. Nonetheless, the causal interconnections with sensorineural hearing loss (SNHL) demand meticulous exploration. Mendelian randomization analysis is a method used in observational epidemiological studies to predict the relationship between exposure factors and outcomes using genetic variants as instrumental variables. In this study, we applied this analytical approach to two distinct samples to predict the causal impact of mitochondrial proteins on SNHL.MethodsTwo-sample Mendelian randomization analyses were executed to scrutinize the predicted associations between 63 mitochondrial proteins (nuclear-encoded) and SNHL, utilizing summary statistics derived from genome-wide association studies. Assessments of pleiotropy and heterogeneity were carried out to gauge the robustness of the obtained findings.ResultsFour mitochondrial proteins exhibited a suggestive causal relationship with the susceptibility to SNHL. Dihydrolipoamide dehydrogenase (DLD; OR = 0.9706, 95% CI = 0.9382–0.9953, p = 0.0230) was linked to a diminished risk of SNHL. Conversely, elevated levels of mitochondrial ribosomal protein L34 (MRPL34; OR = 1.0458, 95% CI = 1.0029–1.0906, p = 0.0362), single-pass membrane protein with aspartate-rich tail 1 (SMDT1; OR = 1.0619, 95% CI = 1.0142–1.1119, p = 0.0104), and superoxide dismutase 2 (SOD2; OR = 1.0323, 95% CI = 1.0020–1.0634, p = 0.0364) were associated with an elevated risk of SNHL.ConclusionThis research utilized Mendelian randomization analysis to predict the relationship between mitochondrial proteins and SNHL. It provides a potential viewpoint on the etiology and diagnosis.

项与 SMDT1 相关的新闻（医药）

2022-08-18

·中国生物技术网

Cell子刊：邱义福团队发现“产热通道”介导的褐色脂肪产热新机制

肥胖已成为全球性的重大健康问题，在个体层面可以通过增加能量消耗来对抗肥胖。自2009年在成人中检测到代谢活跃的褐色/米色脂肪组织（BAT (brown adipose tissue) or beige fat）以来，科学家们一直在寻找增强褐色/米色脂肪产热从而增加能量消耗、抵抗肥胖的方法。褐色脂肪组织线粒体富含解偶联蛋白UCP1（uncoupling protein 1）。UCP1能够提高线粒体内膜对质子的电导性，从而消耗质子梯度，将氧化磷酸化与ATP合成解偶联，把底物氧化的能量转化为热能，以此介导褐色脂肪产热，从而帮助动物抵御低温、肥胖及相关代谢紊乱，是治疗肥胖及代谢疾病的重要靶标。线粒体钙离子单向转运体MCU（mitochondrial calcium uniporter）复合物是负责线粒体钙离子吸收的主要通道。该复合物包含孔道形成亚基MCU以及调节性亚基EMRE（essential MCU regulator）、MICU1/2（mitochondrial calcium uptake 1/2）等。其介导的钙离子吸收促进线粒体有氧呼吸，在三羧酸循环、电子转移、质子梯度累积和ATP合成中发挥关键作用。然而，MCU复合物介导的线粒体钙离子吸收是否调节褐色脂肪产热尚不清楚。2022年8月16日，北京大学未来技术学院/北大-清华生命科学联合中心邱义福团队在Cell Metabolism发表题为The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis的研究论文[1]。该论文首次报道：在肾上腺素能刺激下，褐色脂肪细胞的MCU通过EMRE与UCP1互作，形成MCU-EMRE-UCP1复合物（命名为 “产热通道”，即“thermoporter”）来促进UCP1介导的解偶联呼吸和适应性产热。在该研究中，作者发现：褐色脂肪特异性敲除Mcu或Emre的小鼠表现出寒冷不耐受、褐色脂肪产热能力减弱及UCP1介导的解偶联呼吸受损。作者分离纯化BAT 线粒体中的MCU复合物进行质谱鉴定，发现MCU复合物可能与UCP1存在互作。在BAT线粒体中利用免疫共沉淀、FLAG-Strep串联纯化和blue native PAGE等手段证实了褐色脂肪线粒体上MCU-EMRE-UCP1复合物的存在，并揭示该复合物的形成受肾上腺素能的诱导，且能被PKA急性调控。接下来作者在BAT中定点注射AAV、表达adiponectin启动子驱动的串联蛋白EMRE-UCP1,促进了褐色脂肪线粒体上MCU-EMRE-UCP1复合物的组装。使用钙成像监测成熟褐色脂肪细胞中线粒体的钙离子吸收活性（即MCU活性）发现，去甲肾上腺素刺激可显著增加MCU-EMRE-UCP1复合物的组装并增强MCU活性。增强的线粒体钙离子吸收能够加速TCA循环、增加NADH产生，从而促进UCP1介导的解偶联呼吸和BAT产热。根据MCU-EMRE-UCP1复合物可增强线粒体钙离子吸收、促进解偶联呼吸和产热的特性，作者将其命名为thermoporter（thermogenic uniporter，产热通道）。此外，作者还发现MCU复合物中另外一个重要的调控亚基MICU1可通过抑制thermopoter的组装和功能负向调控产热。最后，作者通过在ob/ob小鼠的BAT中增加thermopoter的组装来提高BAT产热能力，从而改善了ob/ob小鼠的寒冷不耐受。在BAT中增加thermopoter组装还可以帮助野生型小鼠有效对抗高脂饮食诱导的肥胖，提高小鼠的胰岛素敏感性和葡萄糖耐受性，改善小鼠的代谢失调。图一：“产热通道”促进UCP1介导的解偶联呼吸与适应性产热总之，该研究发现褐色脂肪组织中存在MCU-EMRE-UCP1复合物这样一个“产热通道”（thermopoter），并揭示该通道具有响应寒冷和肾上腺素能刺激、增加线粒体钙离子吸收以促进解偶联呼吸和适应性产热的功能（图一）。“产热通道”的发现为肥胖的预防和治疗提供了新靶标。值得注意的是，极少部分的UCP1通过与MCU-EMRE互作形成“产热通道”，却极大地促进了所有UCP1的解偶联呼吸，表明UCP1在解偶联之外还发挥信号分子的作用。论文链接：https://doi.org/10.1016/j.cmet.2022.07.011