Natural underlying mtDNA heteroplasmy as a potential source of intra‐person hiPSC variability
Abstract
Functional variability among human clones of induced pluripotent stem cells (hiPSCs) remains a limitation in assembling high‐quality biorepositories. Beyond inter‐person variability, the root cause of intra‐person variability remains unknown. Mitochondria guide the required transition from oxidative to glycolytic metabolism in nuclear reprogramming. Moreover, mitochondria have their own genome (mitochondrial DNA [mtDNA]). Herein, we performed mtDNA next‐generation sequencing (NGS) on 84 hiPSC clones derived from a cohort of 19 individuals, including mitochondrial and non‐mitochondrial patients. The analysis of mtDNA variants showed that low levels of potentially pathogenic mutations in the original fibroblasts are revealed through nuclear reprogramming, generating mutant hiPSCs with a detrimental effect in their differentiated progeny. Specifically, hiPSC‐derived cardiomyocytes with expanded mtDNA mutations non‐related with any described human disease, showed impaired mitochondrial respiration, being a potential cause of intra‐person hiPSC variability. We propose mtDNA NGS as a new selection criterion to ensure hiPSC quality for drug discovery and regenerative medicine.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 19, 2016
- Source ID
- 10.15252/embj.201694892
Entities
People
- Alexandra N Cook
- Andre Terzic
- Devin Oglesbee
- Eric A. Schon
- Ester Perales‐clemente
- Frank Secreto
- Jared M Evans
- Michio Hirano
- Samantha Roellinger
- Timothy J. Nelson
- Valentina Emmanuele
- Vamsi Mootha
Organizations
- Columbia University
- Leducq Foundation
- Massachusetts General Hospital
- Mayo Clinic
- Muscular Dystrophy Association
- National Institutes of Health
- United States Department of Defense
- University of Messina