Abnormalities of mitochondrial dynamics and bioenergetics in neuronal cells from CDKL5 deficiency disorder

Nicole J. Van Bergen, Sean Massey, Tegan Stait, Molly Ellery, Boris Reljić, Luke E. Formosa, Anita Quigley, Mirella Dottori, David Thorburn, David A. Stroud, John Christodoulou

Research output: Contribution to journalArticleResearchpeer-review


CDKL5 deficiency disorder (CDD) is a rare neurodevelopmental disorder caused by pathogenic variants in the Cyclin-dependent kinase-like 5 (CDKL5) gene, resulting in dysfunctional CDKL5 protein. It predominantly affects females and causes seizures in the first few months of life, ultimately resulting in severe intellectual disability. In the absence of targeted therapies, treatment is currently only symptomatic. CDKL5 is a serine/threonine kinase that is highly expressed in the brain, with a critical role in neuronal development. Evidence of mitochondrial dysfunction in CDD is gathering, but has not been studied extensively. We used human patient-derived induced pluripotent stem cells with a pathogenic truncating mutation (p.Arg59*) and CRISPR/Cas9 gene-corrected isogenic controls, differentiated into neurons, to investigate the impact of CDKL5 mutation on cellular function. Quantitative proteomics indicated mitochondrial defects in CDKL5 p.Arg59* neurons, and mitochondrial bioenergetics analysis confirmed decreased activity of mitochondrial respiratory chain complexes. Additionally, mitochondrial trafficking velocity was significantly impaired, and there was a higher percentage of stationary mitochondria. We propose mitochondrial dysfunction is contributing to CDD pathology, and should be a focus for development of targeted treatments for CDD.
Original languageEnglish
Article number105370
Number of pages14
JournalNeurobiology of Disease
Publication statusPublished - Jul 2021


  • CDKL5
  • CDKL5 deficiency disorder
  • Mitochondria
  • Induced pluripotent stem cell
  • Oxidative phosphorylation
  • Proteomics

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