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

Kirby, Denise, Rennie, Katherine, Smulders-Srinivasan, Tora, Acin-Perez, Rebecca, Whittington, Miles, Enriquez, Jose, Trevelyan, Andrew, Turnbull, Doug and Lightowlers, Robert (2009) Transmitochondrial embryonic stem cells containing pathogenic mtDNA mutations are compromised in neuronal differentiation. Cell Proliferation, 42 (4). pp. 413-424. ISSN 0960-7722

[img]
Preview
PDF (Available under the Creative Commons Attribution 2.5 Generic license)
j.1365-2184.2009.00612.x.pdf - Published Version

Download (522kB) | Preview
Official URL: http://dx.doi.org/10.1111/j.1365-2184.2009.00612.x

Abstract

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.

Item Type: Article
Subjects: C100 Biology
Department: Faculties > Health and Life Sciences > School of Life Sciences > Applied Sciences
Depositing User: Ellen Cole
Date Deposited: 26 Jul 2013 11:09
Last Modified: 08 Feb 2016 19:07
URI: http://nrl.northumbria.ac.uk/id/eprint/13280

Actions (login required)

View Item View Item

Downloads

Downloads per month over past year

View more statistics


Policies: NRL Policies | NRL University Deposit Policy | NRL Deposit Licence