Journal
MITOCHONDRIA AND OXIDATIVE STRESS IN NEURODEGENERATIVE DISORDERS
Volume 1147, Issue -, Pages 254-263Publisher
WILEY-BLACKWELL
DOI: 10.1196/annals.1427.004
Keywords
differentiation; embryonic stem cells; mitochondria; phosphotransfer; energetic communication
Funding
- National Institutes of Health
- Marriott Heart Disease Research Program
- Marriott Foundation
- Ted Nash Long Life Foundation
- Ralph Wilson Medical Research Foundation
- Asper Foundation
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL085744] Funding Source: NIH RePORTER
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Differentiation of pluripotent low-energy requiring stem cells into the high-energy expenditure cardiac lineage requires coordination of genomic programming and energetic system maturation. Here, in a murine embryonic stem cell cardiac differentiation model, emergence of electrical and beating activity in cardiomyocytes developing within embryoid bodies was coupled with the establishment of the mitochondrial network and expansion of the creatine kinase (CK) phosphotransfer system. Stem cell cardiogenesis was characterized by increased total CK activity, ail isoform shift manifested by amplified muscle CK-M mRNA levels and protein content, and the appearance of cardiac-specific CK-MB dimers. Treatment of differentiating stem cells with BMP2, a cardiogenic growth factor, promoted CK activity. CK-M clustered around developing myofibrils, sarcolemma, and the perinuclear compartment, whereas CK-B was tightly associated with myofibrillar a-actinin, forming wire-like structures extending from the nuclear compartment; to the sarcolemma. Developmentally enhanced phosphotransfer enzyme-anchoring protein FHL2 coalesced the myofibrillar CK metabolic signaling circuit, providing an energetic continuum between mitochondria and the nascent contractile machinery. Thus, the evolving CK-catalyzed phosphotransfer network integrates mitochondrial energetics with cardiogenic programming, securing the emergence of energy-consuming cardiac functions in differentiating embryonic stem cells.
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