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Human iPSC disease modelling reveals functional and structural defects in retinal pigment epithelial cells harbouring the m.3243A>G mitochondrial DNA mutation

Lookup NU author(s): Dr Valeria Chichagova, Dr Dean Hallam, Dr Joseph Collin, Dr Adriana BuskinORCiD, Dr Gabriele Saretzki, Professor Lyle Armstrong, Dr Patrick Yu Wai Man, Professor Majlinda LakoORCiD, Professor David SteelORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


The m.3243A>G mitochondrial DNA mutation was originally described in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. The phenotypic spectrum of the m.3243A>G mutation has since expanded to include a spectrum of neuromuscular and ocular manifestations, including reduced vision with retinal degeneration, the underlying mechanism of which remains unclear. We used dermal fibroblasts from patients with retinal pathology secondary to m.3243A>G mutation to generate heteroplasmic induced pluripotent stem cell (hiPSC) clones. RPE cells differentiated from these hiPSCs contained morphologically abnormal mitochondria and melanosomes, and exhibited marked functional defects in phagocytosis of photoreceptor outer segments. These findings have striking similarities to the pathological abnormalities reported in RPE cells studied from post-mortem tissues of affected m.3243A>G mutation carriers. Overall, our results indicate that RPE cells carrying the m.3243A>G mutation have a reduced ability to perform the critical physiological function of phagocytosis. Aberrant melanosomal morphology may potentially have consequences on the ability of the cells to perform another important protective function, namely absorption of stray light. Our in vitro cell model could prove a powerful tool to further dissect the complex pathophysiological mechanisms that underlie the tissue specificity of the m.3243A>G mutation, and importantly, allow the future testing of novel therapeutic agents.

Publication metadata

Author(s): Chichagova V, Hallam D, Collin J, Buskin A, Saretzki G, Armstrong L, Yu-Wai-Man P, Lako M, Steel DH

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2017

Volume: 7

Online publication date: 26/09/2017

Acceptance date: 08/09/2017

Date deposited: 08/09/2017

ISSN (electronic): 2045-2322

Publisher: Nature


DOI: 10.1038/s41598-017-12396-2


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