Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts.
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Authors
Chang, Kai-Ti
Campbell, Alicia N
Stieg, David C
Kiss, Zachary A
Kemper, Kevin
Jiang, Ping
Lee, Hyung-Ok
Kruger, Warren D
van Hasselt, Peter M
Strich, Randy
Publication Date
2022-02-18Journal Title
iScience
ISSN
2589-0042
Publisher
Elsevier BV
Volume
25
Issue
2
Number
ARTN 103823
Pages
103823
Type
Article
This Version
VoR
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Chang, K., Jezek, J., Campbell, A. N., Stieg, D. C., Kiss, Z. A., Kemper, K., Jiang, P., et al. (2022). Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts.. iScience, 25 (2. ARTN 103823), 103823. https://doi.org/10.1016/j.isci.2022.103823
Abstract
MED13L syndrome 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. Unstressed MED13L S1497 F/fs patient 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 of MED13L mutant 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 the MED13L S1497 F/fs allele and identified cyclin C mis-localization as the likely cause. These results provide a new avenue for understanding this disorder.
Keywords
Biochemistry, Biological sciences, Cell biology
Identifiers
External DOI: https://doi.org/10.1016/j.isci.2022.103823
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336118
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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