Abstract 11: Acquisition of Mitochondrial DNA Mutations Impairs Mitochondrial Function in Cardiac Progenitor Cells
Activation of cardiac progenitor cells (CPCs) are critical for effective repair in response to pathologic injury. Stem cell activation and commitment involve increased energy demand and mitochondrial biogenesis. We have previously shown that incubation of c-kit+ CPCs in differentiation medium led to expansion of the mitochondrial network and lineage commitment. CPC function is reduced with age but the underlying mechanism is still unclear. Mitochondria contain their own DNA (mtDNA) which accumulates mutations over time that can impair mitochondrial function. In this study, we investigated the effects of acquiring mtDNA mutations on CPC proliferation, survival, and differentiation. We utilized a mouse model in which a mutation in the mtDNA polymerase gamma (POLGm/m) leads to accumulation of mtDNA mutations, mitochondrial dysfunction, and accelerated aging. Isolated CPCs from hearts of 2-month old POLGm/m mice had reduced proliferation and were more susceptible to oxidative stress and chemotherapeutic agents compared to WT CPCs. Incubation in differentiation medium resulted in fewer lineage committed POLGm/m CPCs compared to WT. In addition, the POLGm/m CPCs failed to activate mitochondrial biogenesis and did not increase levels of proteins involved in mitochondrial oxidative phosphorylation. We measured mitochondrial respiration with the Seahorse XF Analyzer and found that POLGm/m CPCs had undetectable oxygen consumption but still generated similar amounts of ATP as WT CPCs. Interestingly, POLGm/m CPCs produced increased amounts of l-lactate and were more sensitive to 2-deoxyglucose treatment, suggesting that these cells rely on glycolysis for energy production. Both WT and POLGm/m CPCs downregulated expression of glycolytic enzymes during differentiation. However, POLGm/m CPCs failed to undergo the metabolic transition from glycolysis to OXPHOS, which led to activation of cell death during differentiation. These data demonstrate that mitochondria play a critical role in CPC function, and accumulation of mtDNA mutations impairs CPC function and reduces their repair potential.
Author Disclosures: A.M. Orogo: None. E.R. Gonzalez: None. D.A. Kubli: None. A.N. Murphy: None. Å.B. Gustafsson: None.
This research has received full or partial funding support from the American Heart Association, Western States Affiliate (California, Nevada & Utah).
- © 2015 by American Heart Association, Inc.