RNAase III-Type Enzyme Dicer Regulates Mitochondrial Fatty Acid Oxidative Metabolism in Cardiac Mesenchymal Stem Cells.

Xuan Su,Yaoliang Tang,Yue Jin,Neal L Weintraub,Yan Shen,Il-Man Kim

doi:10.3390/ijms20225554

Abstract

Cardiac mesenchymal stem cells (C-MSC) play a key role in maintaining normal cardiac function under physiological and pathological conditions. Glycolysis and mitochondrial oxidative phosphorylation predominately account for energy production in C-MSC. Dicer, a ribonuclease III endoribonuclease, plays a critical role in the control of microRNA maturation in C-MSC, but its role in regulating C-MSC energy metabolism is largely unknown. In this study, we found that Dicer knockout led to concurrent increase in both cell proliferation and apoptosis in C-MSC compared to Dicer floxed C-MSC. We analyzed mitochondrial oxidative phosphorylation by quantifying cellular oxygen consumption rate (OCR), and glycolysis by quantifying the extracellular acidification rate (ECAR), in C-MSC with/without Dicer gene deletion. Dicer gene deletion significantly reduced mitochondrial oxidative phosphorylation while increasing glycolysis in C-MSC. Additionally, Dicer gene deletion selectively reduced the expression of β-oxidation genes without affecting the expression of genes involved in the tricarboxylic acid (TCA) cycle or electron transport chain (ETC). Finally, Dicer gene deletion reduced the copy number of mitochondrially encoded 1,4-Dihydronicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase core subunit 6 (MT-ND6), a mitochondrial-encoded gene, in C-MSC. In conclusion, Dicer gene deletion induced a metabolic shift from oxidative metabolism to aerobic glycolysis in C-MSC, suggesting that Dicer functions as a metabolic switch in C-MSC, which in turn may regulate proliferation and environmental adaptation.

Highlights

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide [1]
We demonstrated that knockout of Dicer in Cardiac mesenchymal stem cells (C-MSC) increased the number of proliferating cells and protein levels of PCNA and p-H3, the markers of cell mitosis, in C-MSC compared to Dicer floxed cells, suggesting that Dicer knockout increased cell proliferation
We found that Dicer gene deletion in C-MSC resulted in a significant reduction in mitochondrial oxidative metabolism, and increased glycolysis; Dicer appears to be important in maintaining fatty acid oxidative metabolism/β-oxidation in C-MSC

Summary

Introduction

Cardiovascular diseases are the leading cause of morbidity and mortality worldwide [1]. In patients with heart failure, disorders of substrate utilization and intermediate metabolism, energy deficiency, and oxidative stress underlie the basis of systolic dysfunction and disease progression [2]. In the normal adult heart, about 70% of ATP production is derived from fatty acid oxidation [3]. To sustain sufficient energy production required to support the continuous mechanical workload, the heart utilizes diverse energy substrates, including glucose and amino acids [4]. Defects in the OXPHOS system can cause a variety of cardiovascular diseases, such as ischemic heart failure, and diabetic cardiomyopathies, in which cardiac mitochondrial dysfunction and impaired energy production have been observed, potentially contributing to a decrease in contractile function and cardiac efficiency [5,6,7]

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Results

Conclusion