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UCP2 modulates cardiomyocyte cell cycle activity, acetyl-CoA, and histone acetylation in response to moderate hypoxia

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Zarka, Clare
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Kurian, Justin
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Harlamova, Daria
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Elia, Andrea
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Kasatkin, Nicole
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Johnson, Jaslyn
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Behanan, Michael
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Pepper, Hannah
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Journal article
Date
2022-06-30
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Center for Metabolic Disease Research (Temple University)
Cardiovascular Research Institute (Temple University)
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Cardiovascular Sciences
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http://hdl.handle.net/20.500.12613/9857
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RigaudEtAl-JournalArticle-2022-06.pdf
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http://dx.doi.org/10.1172/jci.insight.155475
Abstract
Developmental cardiac tissue is regenerative while operating under low oxygen. After birth, ambient oxygen is associated with cardiomyocyte cell cycle exit and regeneration. Likewise, cardiac metabolism undergoes a shift with cardiac maturation. Whether there are common regulators of cardiomyocyte cell cycle linking metabolism to oxygen tension remains unknown. The objective of the study is to determine whether mitochondrial UCP2 is a metabolic oxygen sensor regulating cardiomyocyte cell cycle. Neonatal rat ventricular myocytes (NRVMs) under moderate hypoxia showed increased cell cycle activity and UCP2 expression. NRVMs exhibited a metabolic shift toward glycolysis, reducing citrate synthase, mtDNA, mitochondrial membrane potential (ΔΨm), and DNA damage/oxidative stress, while loss of UCP2 reversed this phenotype. Next, WT and mice from a global UCP2-KO mouse line (UCP2KO) kept under hypoxia for 4 weeks showed significant decline in cardiac function that was more pronounced in UCP2KO animals. Cardiomyocyte cell cycle activity was reduced, while fibrosis and DNA damage was significantly increased in UCP2KO animals compared with WT under hypoxia. Mechanistically, UCP2 increased acetyl-CoA levels and histone acetylation, and it altered chromatin modifiers linking metabolism to cardiomyocyte cell cycle under hypoxia. Here, we show a potentially novel role for mitochondrial UCP2 as an oxygen sensor regulating cardiomyocyte cell cycle activity, acetyl-CoA levels, and histone acetylation in response to moderate hypoxia.
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UCP2 modulates cardiomyocyte cell cycle activity, acetyl-CoA, and histone acetylation in response to moderate hypoxia Vagner O.C. Rigaud, … , Steven R. Houser, Mohsin Khan Published June 30, 2022. JCI Insight. 2022;7(15):e155475. https://doi.org/10.1172/jci.insight.155475.
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American Society for Clinical Investigation
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JCI Insight, Vol. 7, Iss. 15
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