Mitochondrial DNA Dynamics in Reprogramming to Pluripotency

• Published in: Trends in cell biology Vol. 31; no. 4; pp. 311 - 323
• Main Authors: Sercel, Alexander J., Carlson, Natasha M., Patananan, Alexander N., Teitell, Michael A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.04.2021; Elsevier BV
• Subjects: Animals; Cellular Reprogramming - genetics; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; heteroplasmy; induced pluripotent stem cell; Induced Pluripotent Stem Cells; Mitochondria - genetics; Mitochondrial DNA; Mitochondrial Dynamics; Pluripotency; reprogramming; reprogramming; heteroplasmy; pluripotency; induced pluripotent stem cell; mitochondrial DNA
• ISSN: 0962-8924; 1879-3088
• DOI: 10.1016/j.tcb.2020.12.009

Mammalian cells, with the exception of erythrocytes, harbor mitochondria, which are organelles that provide energy, intermediate metabolites, and additional activities to sustain cell viability, replication, and function. Mitochondria contain multiple copies of a circular genome called mitochondrial DNA (mtDNA), whose individual sequences are rarely identical (homoplasmy) because of inherited or sporadic mutations that result in multiple mtDNA genotypes (heteroplasmy). Here, we examine potential mechanisms for maintenance or shifts in heteroplasmy that occur in induced pluripotent stem cells (iPSCs) generated by cellular reprogramming, and further discuss manipulations that can alter heteroplasmy to impact stem and differentiated cell performance. This additional insight will assist in developing more robust iPSC-based models of disease and differentiated cell therapies. iPSCs can differentiate into clinically relevant cell types, but understanding how mtDNA changes with reprogramming and how these changes affect iPSC and progeny metabolism will help to maximize their disease modeling, drug screening, and therapeutic potential.Reprogramming of somatic cells with mtDNA heteroplasmy can yield retained, evenly distributed, or skewed iPSC heteroplasmy ratios that will affect mitochondrial metabolism and potentially cell performance.mtDNA manipulation techniques have potential for controlling the range of mtDNA genotypes within iPSCs and their differentiated progeny cells for desired applications.