Experimental and Molecular Medicine最新文献

Influencing immunity: role of extracellular vesicles in tumor immune checkpoint dynamics. 影响免疫：细胞外囊泡在肿瘤免疫检查点动态中的作用。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-11 DOI: 10.1038/s12276-024-01340-w

Ziyang Ye, Genpeng Li, Jianyong Lei

{"title":"Influencing immunity: role of extracellular vesicles in tumor immune checkpoint dynamics.","authors":"Ziyang Ye, Genpeng Li, Jianyong Lei","doi":"10.1038/s12276-024-01340-w","DOIUrl":"https://doi.org/10.1038/s12276-024-01340-w","url":null,"abstract":"Immune checkpoint proteins (ICPs) serve as critical regulators of the immune system, ensuring protection against damage due to overly activated immune responses. However, within the tumor environment, excessive ICP activation weakens antitumor immunity. Despite the development of numerous immune checkpoint blockade (ICB) drugs in recent years, their broad application has been inhibited by uncertainties about their clinical efficacy. A thorough understanding of ICP regulation in the tumor microenvironment is essential for advancing the development of more effective and safer ICB therapies. Extracellular vesicles (EVs), which are pivotal mediators of cell-cell communication, have been extensively studied and found to play key roles in the functionality of ICPs. Nonetheless, a comprehensive review summarizing the current knowledge about the crosstalk between EVs and ICPs in the tumor environment is lacking. In this review, we summarize the interactions between EVs and several widely studied ICPs as well as their potential clinical implications, providing a theoretical basis for further investigation of EV-related ICB therapeutic approaches.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sorcin can trigger pancreatic cancer-associated new-onset diabetes through the secretion of inflammatory cytokines such as serpin E1 and CCL5. Sorcin 可通过分泌 serpin E1 和 CCL5 等炎性细胞因子引发胰腺癌相关的新发糖尿病。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-08 DOI: 10.1038/s12276-024-01346-4

Jiali Gong, Xiawei Li, Zengyu Feng, Jianyao Lou, Kaiyue Pu, Yongji Sun, Sien Hu, Yizhao Zhou, Tianyu Song, Meihua Shangguan, Kai Zhang, Wenjie Lu, Xin Dong, Jian Wu, Hong Zhu, Qiaojun He, Hongxia Xu, Yulian Wu

{"title":"Sorcin can trigger pancreatic cancer-associated new-onset diabetes through the secretion of inflammatory cytokines such as serpin E1 and CCL5.","authors":"Jiali Gong, Xiawei Li, Zengyu Feng, Jianyao Lou, Kaiyue Pu, Yongji Sun, Sien Hu, Yizhao Zhou, Tianyu Song, Meihua Shangguan, Kai Zhang, Wenjie Lu, Xin Dong, Jian Wu, Hong Zhu, Qiaojun He, Hongxia Xu, Yulian Wu","doi":"10.1038/s12276-024-01346-4","DOIUrl":"https://doi.org/10.1038/s12276-024-01346-4","url":null,"abstract":"A rise in blood glucose is an early warning sign of underlying pancreatic cancer (PC) and may be an indicator of genetic events in PC progression. However, there is still a lack of mechanistic research on pancreatic cancer-associated new-onset diabetes (PCAND). In the present study, we identified a gene SRI, which possesses a SNP with the potential to distinguish PCAND and Type 2 diabetes mellitus (T2DM), by machine learning on the basis of the UK Biobank database. In vitro and in vivo, sorcin overexpression induced pancreatic β-cell dysfunction. Sorcin can form a positive feedback loop with STAT3 to increase the transcription of serpin E1 and CCL5, which may directly induce β-cell dysfunction. In 88 biopsies, the expression of sorcin was elevated in PC tissues, especially in PCAND samples. Furthermore, plasma serpin E1 levels are higher in peripheral blood samples from PCAND patients than in those from T2DM patients. In conclusion, sorcin may be the key driver in PCAND, and further study on the sorcin-STAT3-serpin E1/CCL5 signaling axis may help us better understand the pathogenesis of PCAND and identify potential biomarkers.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The muscle-intervertebral disc interaction mediated by L-BAIBA modulates extracellular matrix homeostasis and PANoptosis in nucleus pulposus cells. 由L-BAIBA介导的肌肉与椎间盘之间的相互作用可调节细胞外基质平衡和髓核细胞的PAN凋亡。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-07 DOI: 10.1038/s12276-024-01345-5

Tianyu Qin, Ming Shi, Chao Zhang, Jiajun Wu, Zhengqi Huang, Xiaohe Zhang, Shuangxing Li, Yuliang Wu, Weitao Han, Bo Gao, Kang Xu, Song Jin, Wei Ye

{"title":"The muscle-intervertebral disc interaction mediated by L-BAIBA modulates extracellular matrix homeostasis and PANoptosis in nucleus pulposus cells.","authors":"Tianyu Qin, Ming Shi, Chao Zhang, Jiajun Wu, Zhengqi Huang, Xiaohe Zhang, Shuangxing Li, Yuliang Wu, Weitao Han, Bo Gao, Kang Xu, Song Jin, Wei Ye","doi":"10.1038/s12276-024-01345-5","DOIUrl":"https://doi.org/10.1038/s12276-024-01345-5","url":null,"abstract":"Upon engaging in physical activity, skeletal muscle synthesizes myokines, which not only facilitate crosstalk with various organs, including the brain, adipose tissue, bone, liver, gut, pancreas, and skin but also promote intramuscular signaling. Crosstalk is vital for maintaining various physiological processes. However, the specific interactions between skeletal muscle and intervertebral discs remain largely unexplored. β-Aminoisobutyric acid (BAIBA), an exercise-induced myokine and a metabolite of branched-chain amino acids in skeletal muscle, has emerged as a key player in this context. Our study demonstrated that exercise significantly elevates BAIBA levels in skeletal muscle, plasma, and nucleus pulposus (NP) tissues. Moreover, exercise enhances extracellular matrix (ECM) synthesis in NP tissues and upregulates L-BAIBA synthase in skeletal muscle. Both in vivo and in vitro evidence revealed that L-BAIBA impedes PANoptosis and ECM degradation in NP cells by activating the AMPK/NF-κB signaling pathway. These findings suggest that exercise, coupled with the resulting increase in L-BAIBA, may serve as an effective intervention to decelerate the progression of intervertebral disc degeneration (IDD). Consequently, L-BAIBA, which originates from skeletal muscle, is a promising new therapeutic approach for IDD.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lactate utilization in Lace1 knockout mice promotes browning of inguinal white adipose tissue. Lace1 基因敲除小鼠对乳酸的利用可促进腹股沟白色脂肪组织的棕色化。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-07 DOI: 10.1038/s12276-024-01324-w

Youn Ju Kim, Sang Gyu Lee, Su In Jang, Won Kon Kim, Kyoung-Jin Oh, Kwang-Hee Bae, Hye Jin Kim, Je Kyung Seong

{"title":"Lactate utilization in Lace1 knockout mice promotes browning of inguinal white adipose tissue.","authors":"Youn Ju Kim, Sang Gyu Lee, Su In Jang, Won Kon Kim, Kyoung-Jin Oh, Kwang-Hee Bae, Hye Jin Kim, Je Kyung Seong","doi":"10.1038/s12276-024-01324-w","DOIUrl":"https://doi.org/10.1038/s12276-024-01324-w","url":null,"abstract":"Recent studies have focused on identifying novel genes involved in the browning process of inguinal white adipose tissue (iWAT). In this context, we propose that the mitochondrial ATPase gene lactation elevated 1 (Lace1) utilizes lactate to regulate the browning capacity of iWAT, specifically in response to challenge with CL-316,243 (CL), a beta3-adrenergic receptor (β3-AR) agonist. The mice were injected with CL over a span of 3 days and exposed to cold temperatures (4-6 °C) for 1 week. The results revealed a significant increase in Lace1 expression levels during beige adipogenesis. Additionally, a strong positive correlation was observed between Lace1 and Ucp1 mRNA expression in iWAT under browning stimulation. To further explore this phenomenon, we subjected engineered Lace1 KO mice to CL and cold challenges to validate their browning potential. Surprisingly, Lace1 KO mice presented increased oxygen consumption and heat generation upon CL challenge and cold exposure, along with increased expression of genes related to brown adipogenesis. Notably, deletion of Lace1 led to increased lactate uptake and browning in iWAT under CL challenge compared with those of the controls. These unique phenomena stem from increased lactate release due to the inactivation of pyruvate dehydrogenase (PDH) in the hearts of Lace1 KO mice.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SUMOylation of TP53INP1 is involved in miR-30a-5p-regulated heart senescence. TP53INP1 的 SUMOylation 参与了 miR-30a-5p 调控的心脏衰老。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-07 DOI: 10.1038/s12276-024-01347-3

Yi-Xiang Hong, Chan Wu, Jing-Zhou Li, Fei Song, Yu Hu, Yue Han, Yi-Jie Mao, Wei-Yin Wu, Yan Wang, Gang Li

{"title":"SUMOylation of TP53INP1 is involved in miR-30a-5p-regulated heart senescence.","authors":"Yi-Xiang Hong, Chan Wu, Jing-Zhou Li, Fei Song, Yu Hu, Yue Han, Yi-Jie Mao, Wei-Yin Wu, Yan Wang, Gang Li","doi":"10.1038/s12276-024-01347-3","DOIUrl":"https://doi.org/10.1038/s12276-024-01347-3","url":null,"abstract":"Heart senescence is critical for cardiac function. This study aimed to characterize the role and mechanism of action of miR-30a-5p in cardiac senescence. miR-30a-5p was downregulated in aged mouse hearts and neonatal rat cardiomyocytes (NRCMs). In vivo, using a combination of echocardiography and different molecular biological approaches, we investigated the role of miR-30a-5p knockout or overexpression in natural- or D-galactose-induced heart aging in mice. In vitro, using RNA sequencing and a series of molecular biology methods, the mechanism by which miR-30a-5p regulates cardiac senescence was explored in cardiomyocytes. miR-30a-5p knockout mice showed aggravated natural- or D-galactose-induced heart aging compared to wild-type littermate mice, with significantly decreased heart function, an increased number of γH2AX-positive cells, reduced telomere length, and upregulated p21 and p53 expression. Cardiac-specific knockdown of miR-30a-5p using adeno-associated virus 9 in D-galactose-induced senescent wild-type mice resulted in effects similar to those observed in knockout mice. Notably, the overexpression of miR-30a-5p in wild-type murine hearts alleviated D-galactose-induced heart senescence by improving heart function, increasing telomere length, decreasing the number of γH2AX-positive cells, and downregulating p53 and p21 expression. This was confirmed in D-galactose-treated or naturally aged NRCMs. Mechanistically, TP53INP1 was identified as a target of miR-30a-5p by mediating the SUMOylation of TP53INP1 and its translocation from the cytoplasm to the nucleus to interact with p53. Furthermore, this study demonstrated that cardiac-specific TP53INP1 deficiency ameliorates miR-30a-5p knockout-aggravated cardiac dysfunction and heart senescence. This study identified miR-30a-5p as a crucial modulator of heart senescence and revealed that the miR-30a-5p-TP53INP1-p53 axis is essential for heart and cardiomyocyte aging.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cells and signals of the leukemic microenvironment that support progression of T-cell acute lymphoblastic leukemia (T-ALL). 支持 T 细胞急性淋巴细胞白血病 (T-ALL) 进展的白血病微环境细胞和信号。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-01 DOI: 10.1038/s12276-024-01335-7

Aram Lyu, Seo Hee Nam, Ryan S Humphrey, Terzah M Horton, Lauren I R Ehrlich

{"title":"Cells and signals of the leukemic microenvironment that support progression of T-cell acute lymphoblastic leukemia (T-ALL).","authors":"Aram Lyu, Seo Hee Nam, Ryan S Humphrey, Terzah M Horton, Lauren I R Ehrlich","doi":"10.1038/s12276-024-01335-7","DOIUrl":"https://doi.org/10.1038/s12276-024-01335-7","url":null,"abstract":"Current intensified chemotherapy regimens have significantly increased survival rates for pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL), but these treatments can result in serious adverse effects; furthermore, patients who are resistant to chemotherapy or who relapse have inferior outcomes, together highlighting the need for improved therapeutic strategies. Despite recent advances in stratifying T-ALL into molecular subtypes with distinct driver mutations, efforts to target the tumor-intrinsic genomic alterations critical for T-ALL progression have yet to translate into more effective and less toxic therapies. Ample evidence now indicates that extrinsic factors in the leukemic microenvironment are critical for T-ALL growth, infiltration, and therapeutic resistance. Considering the diversity of organs infiltrated by T-ALL cells and the unique cellular components of the microenvironment encountered at each site, it is likely that there are both shared features of tumor-supportive niches across multiple organs and site-specific features that are key to leukemia cell survival. Therefore, elucidating the distinct microenvironmental cues supporting T-ALL in different anatomic locations could reveal novel therapeutic targets to improve therapies. This review summarizes the current understanding of the intricate interplay between leukemia cells and the diverse cells they encounter within their tumor microenvironments (TMEs), as well as opportunities to therapeutically target the leukemic microenvironment.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteogenomic analysis dissects early-onset breast cancer patients with prognostic relevance. 蛋白质基因组分析剖析了与预后相关的早期乳腺癌患者。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-01 DOI: 10.1038/s12276-024-01332-w

Kyong-Ah Yoon, Youngwook Kim, So-Youn Jung, Jin-Sun Ryu, Kyung-Hee Kim, Eun-Gyeong Lee, Heejung Chae, Youngmee Kwon, Jaegil Kim, Jong Bae Park, Sun-Young Kong

{"title":"Proteogenomic analysis dissects early-onset breast cancer patients with prognostic relevance.","authors":"Kyong-Ah Yoon, Youngwook Kim, So-Youn Jung, Jin-Sun Ryu, Kyung-Hee Kim, Eun-Gyeong Lee, Heejung Chae, Youngmee Kwon, Jaegil Kim, Jong Bae Park, Sun-Young Kong","doi":"10.1038/s12276-024-01332-w","DOIUrl":"https://doi.org/10.1038/s12276-024-01332-w","url":null,"abstract":"Early-onset breast cancer is known for its aggressive clinical characteristics and high prevalence in East Asian countries, but a comprehensive understanding of its molecular features is still lacking. In this study, we conducted a proteogenomic analysis of 126 treatment-naïve primary tumor tissues obtained from Korean patients with young breast cancer (YBC) aged ≤40 years. By integrating genomic, transcriptomic, and proteomic data, we identified five distinct functional subgroups that accurately represented the clinical characteristics and biological behaviors of patients with YBC. Our integrated approach could be used to determine the proteogenomic status of HER2, enhancing its clinical significance and prognostic value. Furthermore, we present a proteome-based homologous recombination deficiency (HRD) analysis that has the potential to overcome the limitations of conventional genomic HRD tests, facilitating the identification of new patient groups requiring targeted HR deficiency treatments. Additionally, we demonstrated that protein-RNA correlations can be used to predict the late recurrence of hormone receptor-positive breast cancer. Within each molecular subtype of breast cancer, we identified functionally significant protein groups whose differential abundance was closely correlated with the clinical progression of breast cancer. Furthermore, we derived a recurrence predictive index capable of predicting late recurrence, specifically in luminal subtypes, which plays a crucial role in guiding decisions on treatment durations for YBC patients. These findings improve the stratification and clinical implications for patients with YBC by contributing to the optimal adjuvant treatment and duration for favorable clinical outcomes.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interplay between membranes and biomolecular condensates in the regulation of membrane-associated cellular processes. 膜与生物分子凝聚物在调节膜相关细胞过程中的相互作用。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-01 DOI: 10.1038/s12276-024-01337-5

Nari Kim, Hyeri Yun, Hojin Lee, Joo-Yeon Yoo

引用次数: 0

Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice. 小鼠线粒体 ND5 无义突变的综合表型评估。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-01 DOI: 10.1038/s12276-024-01333-9

Sanghun Kim, Seul Gi Park, Jieun Kim, Seongho Hong, Sang-Mi Cho, Soo-Yeon Lim, Eun-Kyoung Kim, Sungjin Ju, Su Bin Lee, Sol Pin Kim, Tae Young Jeong, Yeji Oh, Seunghun Han, Hae-Rim Kim, Taek Chang Lee, Hyoung-Chin Kim, Won Kee Yoon, Tae Hyeon An, Kyoung-Jin Oh, Ki-Hoan Nam, Seonghyun Lee, Kyoungmi Kim, Je Kyung Seong, Hyunji Lee

{"title":"Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice.","authors":"Sanghun Kim, Seul Gi Park, Jieun Kim, Seongho Hong, Sang-Mi Cho, Soo-Yeon Lim, Eun-Kyoung Kim, Sungjin Ju, Su Bin Lee, Sol Pin Kim, Tae Young Jeong, Yeji Oh, Seunghun Han, Hae-Rim Kim, Taek Chang Lee, Hyoung-Chin Kim, Won Kee Yoon, Tae Hyeon An, Kyoung-Jin Oh, Ki-Hoan Nam, Seonghyun Lee, Kyoungmi Kim, Je Kyung Seong, Hyunji Lee","doi":"10.1038/s12276-024-01333-9","DOIUrl":"https://doi.org/10.1038/s12276-024-01333-9","url":null,"abstract":"Mitochondrial dysfunction induced by mitochondrial DNA (mtDNA) mutations has been implicated in various human diseases. A comprehensive analysis of mitochondrial genetic disorders requires suitable animal models for human disease studies. While gene knockout via premature stop codons is a powerful method for investigating the unique functions of target genes, achieving knockout of mtDNA has been rare. Here, we report the genotypes and phenotypes of heteroplasmic MT-ND5 gene-knockout mice. These mutant mice presented damaged mitochondrial cristae in the cerebral cortex, hippocampal atrophy, and asymmetry, leading to learning and memory abnormalities. Moreover, mutant mice are susceptible to obesity and thermogenetic disorders. We propose that these mtDNA gene-knockdown mice could serve as valuable animal models for studying the MT-ND5 gene and developing therapies for human mitochondrial disorders in the future.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss. MYH1 缺乏症会破坏外毛细胞的电流动性，导致听力损失。

IF 9.5 2区医学

Experimental and Molecular Medicine Pub Date : 2024-11-01 DOI: 10.1038/s12276-024-01338-4

Jinsei Jung, Sun Young Joo, Hyehyun Min, Jae Won Roh, Kyung Ah Kim, Ji-Hyun Ma, John Hoon Rim, Jung Ah Kim, Se Jin Kim, Seung Hyun Jang, Young Ik Koh, Hye-Youn Kim, Ho Lee, Byoung Choul Kim, Heon Yung Gee, Jinwoong Bok, Jae Young Choi, Je Kyung Seong

{"title":"MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss.","authors":"Jinsei Jung, Sun Young Joo, Hyehyun Min, Jae Won Roh, Kyung Ah Kim, Ji-Hyun Ma, John Hoon Rim, Jung Ah Kim, Se Jin Kim, Seung Hyun Jang, Young Ik Koh, Hye-Youn Kim, Ho Lee, Byoung Choul Kim, Heon Yung Gee, Jinwoong Bok, Jae Young Choi, Je Kyung Seong","doi":"10.1038/s12276-024-01338-4","DOIUrl":"https://doi.org/10.1038/s12276-024-01338-4","url":null,"abstract":"Myh1 is a mouse deafness gene with an unknown function in the auditory system. Hearing loss in Myh1-knockout mice is characterized by an elevated threshold for the auditory brainstem response and the absence of a threshold for distortion product otoacoustic emission. Here, we investigated the role of MYH1 in outer hair cells (OHCs), crucial structures in the organ of Corti responsible for regulating cochlear amplification. Direct whole-cell voltage-clamp recordings of OHCs revealed that prestin activity was lower in Myh1-knockout mice than in wild-type mice, indicating abnormal OHC electromotility. We analyzed whole-exome sequencing data from 437 patients with hearing loss of unknown genetic causes and identified biallelic missense variants of MYH1 in five unrelated families. Hearing loss in individuals harboring biallelic MYH1 variants was non-progressive, with an onset ranging from congenital to childhood. Three of five individuals with MYH1 variants displayed osteopenia. Structural prediction by AlphaFold2 followed by molecular dynamic simulations revealed that the identified variants presented structural abnormalities compared with wild-type MYH1. In a heterogeneous overexpression system, MYH1 variants, particularly those in the head domain, abolished MYH1 functions, such as by increasing prestin activity and modulating the membrane traction force. Overall, our findings suggest an essential function of MYH1 in OHCs, as observed in Myh1-deficient mice, and provide genetic evidence linking biallelic MYH1 variants to autosomal recessive hearing loss in humans.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0