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Transmitochondrial embryonic stem cells containing pathogenic mtDNA mutations are compromised in neuronal differentiation

Lookup NU author(s): Dr Denise Kirby, Dr Kate Rennie, Dr Tora Smulders-Srinivasan, Professor Miles Whittington, Professor Andrew Trevelyan, Emeritus Professor Doug Turnbull, Professor Robert Lightowlers



Objectives: Defects of the mitochondrial genome (mtDNA) cause a series of rare, mainly neurological disorders. In addition, they have been implicated in more common forms of movement disorders, dementia and the ageing process. In order to try to model neuronal dysfunction associated with mitochondrial disease, we have attempted to establish a series of transmitochondrial mouse embryonic stem cells harbouring pathogenic mtDNA mutations. Materials and methods: Transmitochondrial embryonic stem cell cybrids were generated by fusion of cytoplasts carrying a variety of mtDNA mutations, into embryonic stem cells that had been pretreated with rhodamine 6G, to prevent transmission of endogenous mtDNA. Cybrids were differentiated into neurons and assessed for efficiency of differentiation and electrophysiological function. Results: Neuronal differentiation could occur, as indicated by expression of neuronal markers. Differentiation was impaired in embryonic stem cells carrying mtDNA mutations that caused severe biochemical deficiency. Electrophysiological tests showed evidence of synaptic activity in differentiated neurons carrying non-pathogenic mtDNA mutations or in those that caused a mild defect of respiratory activity. Again, however, neurons carrying mtDNA mutations that resulted in severe biochemical deficiency had marked reduction in post-synaptic events. Conclusions: Differentiated neurons carrying severely pathogenic mtDNA defects can provide a useful model for understanding how such mutations can cause neuronal dysfunction.

Publication metadata

Author(s): Kirby DM, Rennie KJ, Smulders-Srinivasan TK, Acin-Perez R, Whittington M, Enriquez JA, Trevelyan AJ, Turnbull DM, Lightowlers RN

Publication type: Article

Publication status: Published

Journal: Cell Proliferation

Year: 2009

Volume: 42

Issue: 4

Pages: 413-424

Date deposited: 10/06/2010

ISSN (print): 0960-7722

ISSN (electronic): 1365-2184

Publisher: Wiley-Blackwell Publishing Ltd.


DOI: 10.1111/j.1365-2184.2009.00612.x


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Funder referenceFunder name
NHMRC CJ Martin Postdoctoral Fellowship
074454/Z/04/ZWellcome Trust
LSJM-CT-2004-503116European Commission