Study of mitochondrial respiratory defects on reprogramming to human induced pluripotent stem cells

Reprogramming of somatic cells into a pluripotent state is known to be accompanied by extensive restructuring of mitochondria and switch in metabolic requirements. Here we utilized Leber's hereditary optic neuropathy (LHON) as a mitochondrial disease model to study the effects of homoplasmic mt...

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Veröffentlicht in:Aging (Albany, NY.) Jg. 8; H. 5; S. 945
Hauptverfasser: Hung, Sandy S C, Van Bergen, Nicole J, Jackson, Stacey, Liang, Helena, Mackey, David A, Hernández, Damián, Lim, Shiang Y, Hewitt, Alex W, Trounce, Ian, Pébay, Alice, Wong, Raymond C B
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.05.2016
Schlagworte:
Cellular Reprogramming
DNA, Mitochondrial
Fibroblasts - metabolism
Humans
Induced Pluripotent Stem Cells - metabolism
Mitochondria - metabolism
Optic Atrophy, Hereditary, Leber - metabolism
Organelle Biogenesis
Oxidative Phosphorylation
Leber's hereditary optic neuropathy
induced pluripotent stem cells
mitochondria
oxidative phosphorylation
cellular reprogramming
ISSN:1945-4589, 1945-4589
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Zusammenfassung:Reprogramming of somatic cells into a pluripotent state is known to be accompanied by extensive restructuring of mitochondria and switch in metabolic requirements. Here we utilized Leber's hereditary optic neuropathy (LHON) as a mitochondrial disease model to study the effects of homoplasmic mtDNA mutations and subsequent oxidative phosphorylation (OXPHOS) defects in reprogramming. We obtained fibroblasts from a total of 6 LHON patients and control subjects, and showed a significant defect in complex I respiration in LHON fibroblasts by high-resolution respiratory analysis. Using episomal vector reprogramming, our results indicated that human induced pluripotent stem cell (hiPSC) generation is feasible in LHON fibroblasts. In particular, LHON-specific OXPHOS defects in fibroblasts only caused a mild reduction and did not significantly affect reprogramming efficiency, suggesting that hiPSC reprogramming can tolerate a certain degree of OXPHOS defects. Our results highlighted the induction of genes involved in mitochondrial biogenesis (TFAM, NRF1), mitochondrial fusion (MFN1, MFN2) and glycine production (GCAT) during reprogramming. However, LHON-associated OXPHOS defects did not alter the kinetics or expression levels of these genes during reprogramming. Together, our study provides new insights into the effects of mtDNA mutation and OXPHOS defects in reprogramming and genes associated with various aspects of mitochondrial biology.
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ISSN:1945-4589
1945-4589
DOI:10.18632/aging.100950