Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts

Kai-Ti Chang; Jan Jezek; Alicia N Campbell; David C Stieg; Zachary A Kiss; Kevin Kemper; Ping Jiang; Hyung-Ok Lee; Warren D Kruger; Peter M van Hasselt; Randy Strich

doi:10.1016/j.isci.2022.103823

Aberrant cyclin C nuclear release induces mitochondrial fragmentation and dysfunction in MED13L syndrome fibroblasts

iScience. 2022 Jan 30;25(2):103823. doi: 10.1016/j.isci.2022.103823. eCollection 2022 Feb 18.

Authors

Affiliations

¹ Department of Molecular Biology, Graduate School of Biomedical Sciences, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
² Department of Medicine, Rowan University School of Osteopathic Medicine, Stratford, NJ 08084, USA.
³ Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
⁴ Department of Metabolic and Endocrine Disease, University of Utrecht Medical Center, Utrecht, 3584 CX, the Netherlands.

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.