文章基本信息

标题：Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts
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作者：Kai-Ti Chang ; Jan Jezek ; Alicia N. Campbell 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：2
页码：1-17
DOI：10.1016/j.isci.2022.103823
语种：English
出版社：Elsevier
摘要：SummaryMED13Lsyndrome is a haploinsufficiency developmental disorder characterized by intellectual disability, heart malformation, and hypotonia. MED13L controls transcription by tethering the cyclin C-Cdk8 kinase module (CKM) to the Mediator complex. In addition, cyclin C has CKM-independent roles in the cytoplasm directing stress-induced mitochondrial fragmentation and regulated cell death. UnstressedMED13LS1497F/fspatient fibroblasts exhibited aberrant cytoplasmic cyclin C localization, mitochondrial fragmentation, and a 6-fold reduction in respiration. In addition, the fibroblasts exhibited reduced mtDNA copy number, reduction in mitochondrial membrane integrity, and hypersensitivity to oxidative stress. Finally, transcriptional analysis ofMED13Lmutant fibroblasts revealed reduced mRNA levels for several genes necessary for normal mitochondrial function. Pharmacological or genetic approaches preventing cyclin C-mitochondrial localization corrected the fragmented mitochondrial phenotype and partially restored organelle function. In conclusion, this study found that mitochondrial dysfunction is an underlying defect in cells harboring theMED13LS1497F/fsallele and identified cyclin C mis-localization as the likely cause. These results provide a new avenue for understanding this disorder.Graphical abstractDisplay OmittedHighlights•MED13Lhaplo-insufficiency mutation causes aberrant cyclin C nuclear release•Cyclin C nuclear release fragments mitochondria and increases endogenous ROS•MED13L syndrome patient fibroblasts exhibit reduced mitochondrial function•MED13L syndrome patient fibroblasts exhibit reduced mtDNA copy numberBiological sciences; Biochemistry; Cell biology