Abstract
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.
Highlights
Recent advances in reprogramming of somatic cells into human induced pluripotent stem cells provide tremendous potential for disease modeling, drug discovery and gene therapy development
While pluripotent stem cells mainly utilize anaerobic glycolysis for energy production, somatic differentiated cells primarily rely on aerobic metabolism by oxidative phosphorylation (OXPHOS) for energy production [20]
We focused on the role of mitochondrial OXPHOS in the induction of pluripotency during reprogramming. human induced pluripotent stem cell (hiPSC) have been successfully generated from a range of mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, including MELAS [22
Summary
Recent advances in reprogramming of somatic cells into human induced pluripotent stem cells (hiPSCs) provide tremendous potential for disease modeling, drug discovery and gene therapy development. Previous reports showed that the process of reprogramming can ‘rejuvenate’ somatic cells and erase many aging signatures, such as age-associated mitochondrial respiration defects [1], aging gene profile and nuclearcytoplasmic compartmentalization [2]. Understanding the mechanisms involved in reprogramming may provide valuable insights into the aging process. Mitochondrial oxidative phosphorylation (OXPHOS), mediated by the electron transport chain to generate ATP, provides a major source of cellular energy. The impact of OXPHOS defects in the reprogramming process remains understudied. Mitochondrial impairment is involved in many pathological diseases and in aging [3]. The mitochondrial DNA (mtDNA) mutator mice, which www.impactaging.com
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