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Stem Cells and Mitochondria

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Mitochondria and Their Role in Cardiovascular Disease

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Abstract

Stem cells are undifferentiated cells characterized by the presence of the potential for self-renewal and the unique ability to differentiate into various cell types—pluripotency. Various cell types proposed as candidates for cardiac cell-based therapy can be divided into two groups: allogenic and autologous according to their origin. Allogenic cells include embryonic stem cells (ESCs), fetal cardiomyocytes, and umbilical cord-derived cells, whereas autologous or adult stem cells include bone-marrow- and adipose-derived stem cells, skeletal myoblasts, resident cardiac progenitor cells, and induced pluripotent stem cells (iPSCs). Different cell types and delivery strategies have been examined in experimental and clinical settings; however, neither the ideal cell type nor cell delivery method for cardiac cell therapy has yet emerged.

Emerging evidence suggests that mitochondria play an essential role in ESC maintenance and differentiation. Undifferentiated ESCs and iPSCs contain the decreased number of immature mitochondria displaying perinuclear localization. Levels of mtDNA and factors, implicated in mtDNA maintenance, are also significantly diminished. Early embryos, undifferentiated ESCs, and iPSCs typically exhibit prevalence of anaerobic glycolysis as the major energy source. Expression of glycolytic enzymes is upregulated, whereas expression of subunits of ETC is downregulated resulting in lower O2 consumption and lower levels of intracellular ATP. Upon ESC differentiation into cardiomyocytes, the expression of glycolytic enzymes is downregulated, while the expression of OXPHOS subunits and citric acid cycle enzymes is upregulated. Hence O2 consumption, OXPHOS, and ATP generation are significantly increased, mtDNA replication and mitochondrial biogenesis are resumed, and mature mitochondrial networks are formed.

Switch in energy metabolism from glycolysis to OXPHOS during differentiation of ESCs can lead to increase in intracellular levels of reactive oxygen species (ROS). The upregulation of the antioxidant system in differentiating ESCs does not compensate the increased generation of ROS. Accumulation of oxidative damages in mtDNA in differentiating ESCs leads to mutations in mitochondrial genomes affecting ATP production, Ca2+ homeostasis, cell proliferation and differentiation resulting subsequently in apoptosis. ROS also play an important role as a critical signaling intermediate implicated in control of ESC proliferation and differentiation. ROS-induced deacetylase silent information regulator 1 (SIRT1) activation contributes to ESC maintenance by both inducing mitochondria-mediated apoptosis of damaged cells and by attenuating p53-mediated inhibition of the pluripotent factor Nanog. The p53-telomere axis appears to be also involved in this complex regulatory circuitry. Further insights gleaned from study of mitochondrial function in stem cells will no doubt accelerate the design of realistic clinical cell-based therapy for cardiovascular disorders.

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  1. The Molecular Cardiology and Neuromuscular Institute, Highland Park, NJ, USA

    José Marín-García M.D.

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Marín-García, J. (2013). Stem Cells and Mitochondria. In: Mitochondria and Their Role in Cardiovascular Disease. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-4599-9_9

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