The Small GTPases Rab27b Regulates Mitochondrial Fatty Acid Oxidative Metabolism of Cardiac Mesenchymal Stem Cells

Jin, Yue; Shen, Yan; Su, Xuan; Cai, Jingwen; Liu, Yutao; Weintraub, Neal L.; Tang, Yaoliang

doi:10.3389/fcell.2020.00209

Cited by 12 publications

(12 citation statements)

References 47 publications

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“…OCR and ECAR were quantified using Seahorse XF 96 extracellular flux analyzer (Agilent Technologies, Lexington, MA, USA) as previously described with minor modifications (18,19). Briefly, the cells were plated at 10,000 cells/well in the Seahorse XF cell culture microplate.…”

Section: Seahorse Analysis Of Mitochondrial Respirometrymentioning

confidence: 99%

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The Impaired Bioenergetics of Diabetic Cardiac Microvascular Endothelial Cells

et al. 2021

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Diabetes causes hyperglycemia, which can create a stressful environment for cardiac microvascular endothelial cells (CMECs). To investigate the impact of diabetes on the cellular metabolism of CMECs, we assessed glycolysis by quantifying the extracellular acidification rate (ECAR), and mitochondrial oxidative phosphorylation (OXPHOS) by measuring cellular oxygen consumption rate (OCR), in isolated CMECs from wild-type (WT) hearts and diabetic hearts (db/db) using an extracellular flux analyzer. Diabetic CMECs exhibited a higher level of intracellular reactive oxygen species (ROS), and significantly reduced glycolytic reserve and non-glycolytic acidification, as compared to WT CMECs. In addition, OCR assay showed that diabetic CMECs had increased maximal respiration, and significantly reduced non-mitochondrial oxygen consumption and proton leak. Quantitative PCR (qPCR) showed no difference in copy number of mitochondrial DNA (mtDNA) between diabetic and WT CMECs. In addition, gene expression profiling analysis showed an overall decrease in the expression of essential genes related to β-oxidation (Sirt1, Acox1, Acox3, Hadha, and Hadhb), tricarboxylic acid cycle (TCA) (Idh-3a and Ogdh), and electron transport chain (ETC) (Sdhd and Uqcrq) in diabetic CMECs compared to WT CMECs. Western blot confirmed that the protein expression of Hadha, Acox1, and Uqcrq was decreased in diabetic CMECs. Although lectin staining demonstrated no significant difference in capillary density between the hearts of WT mice and db/db mice, diabetic CMECs showed a lower percentage of cell proliferation by Ki67 staining, and a higher percentage of cellular apoptosis by TUNEL staining, compared with WT CMECs. In conclusion, excessive ROS caused by hyperglycemia is associated with impaired glycolysis and mitochondrial function in diabetic CMECs, which in turn may reduce proliferation and promote CMEC apoptosis.

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Section: Seahorse Analysis Of Mitochondrial Respirometrymentioning

confidence: 99%

“…Western blotting was performed as previously described (18,19). Briefly, the protein samples were separated on 10% SDSpolyacrylamide gels, and the gel was then transferred onto nitrocellulose membranes (LI-COR Biosciences).…”

Section: Western Blotting Assaymentioning

confidence: 99%

The Impaired Bioenergetics of Diabetic Cardiac Microvascular Endothelial Cells

et al. 2021

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“…Mitochondrial fatty acid oxidation is the main source of ATP in many tissues and organs [34]. Fatty acid oxidation is a complex biological process involving mitochondrial β-oxidation, tricarboxylic acid cycle activity, and the electron transport chain [35]. Alterations in fatty acid metabolism can contribute to a variety of pathologies and cell dysfunction [36].…”

Section: Discussionmentioning

confidence: 99%

High-Fat Diet-Induced Obesity Primes Impaired Fatty Acid β-Oxidation and Consequent Ovarian Dysfunction During Early Pregnancy

Qingying¹,

Guo²,

Yang³

et al. 2021

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Background: Obesity is associated with many adverse effects on female fertility. Obese women are more likely to have ovulatory dysfunction due to dysregulation of the hypothalamic-pituitary-ovarian axis. However, ovarian function in obese women during early pregnancy still needs further assessment. Methods: Obesity was induced in C57BL6/J mice using high-fat diets (HFD) for 12 weeks; In vitro high-fat model was established with KGN cells treated with Oleate acid and Palmitic acid. Ovarian morphology of obese mice in early pregnancy was assessed by Hematoxylin and Eosin staining and its function was assessed using ELISA, Western blotting and Immunohistochemistry. The Oil Red O staining and Transmission electron microscopy were used to detect fatty acid accumulation and specific markers relating to ovarian functional mechanism were assessed by Real time PCR, Western blotting, Lactate detection, ATP detection, Biochemical analyses and ELISA.Results: The results of this study showed that during early pregnancy, the number of corpus luteum, serum estradiol and progesterone levels, and the expression of genes CYP19A1, CYP11A1 and StAR, which are related to steroid biosynthesis, were significantly increased in HFD female mice. HFD-fed mice also showed a significant increase in ovarian lipid accumulation on day 7 of pregnancy. Genes involved in fatty acid synthesis (Acsl4 and Elovl5) and fatty acid uptake and transport (Slc27a4), together with the β-oxidation rate-limiting enzyme (Cpt1a) were significantly upregulated in HFD-fed mice. Specifically, there was abnormal elevation of ATP level and aberrant expression of tricarboxylic acid cycle (TCA) and electron transport chain related genes in the ovary of HFD pregnant mice. Treatment of KGN cells with etomoxir targeting β-oxidation of fatty acid, showed decrease tricarboxylic acid cycle and electron transport chain. The elevated ATP level and the increased estradiol and progesterone levels were reversed. Conclusions: This study indicated that during early pregnancy, high-fat diet and induced-obesity increased fatty acid β-oxidation, which in turn increase the tricarboxylic acid cycle and the electron transport chain, and consequently increases ATP production and ovarian dysfunction.

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“…In addition, treating AD-MSCs with mangiferin, a class of flavonoids extracted from mango, could improve the mitochondrial respiratory function by increasing the expression of mitochondrial OCR and OXPHOS-related proteins, thereby inducing the AD-MSCs to differentiate into brown adipocytes and improve obesity [ 67 ]. Rab27b, a member of the small GTPases family, can increase the OXPHOS in cardiac mesenchymal stem cells (C-MSCs) and significantly reduce mitochondrial glycolysis; consequently, this maintains the fatty acid oxidative metabolism of the C-MSCs, suggesting that regulatory genes and drugs may ultimately play a therapeutic role by affecting the mitochondrial energy metabolism [ 68 ]. However, recent studies have reported that canagliflozin, a therapeutic medicine for type 2 diabetes, can inhibit the activity of glutamate dehydrogenase 1, which interferes with mitochondrial OXPHOS and ATP production; consequently, it inhibits the proliferation and migration of the BMSCs, which may lead to a decline in the tissue repair ability of the transplanted BMSCs.…”

Section: The Role Of Mitochondrial Energy Metabolism In the Regulatiomentioning

confidence: 99%

“…Unlike their differentiated states, the MSCs in their undifferentiated states have low levels of intra-cellular ROS and high levels of antioxidant enzymes [ 79 ]. Studies have reported that excessive ROS levels can impair the osteogenic differentiation ability of the MSCs [ 68 , 80 ]. However, in the adipogenic differentiation of the MSCs, the production and increase in the ROS levels is not only a result of the adipocyte differentiation, but also one of the conditions for the adipogenic differentiation of the MSCs.…”

Section: The Role Of Mitochondrial Energy Metabolism In the Regulatiomentioning

confidence: 99%

The role and mechanism of mitochondrial functions and energy metabolism in the function regulation of the mesenchymal stem cells

2021

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Mesenchymal stem cells (MSCs) are multipotent cells that show self-renewal, multi-directional differentiation, and paracrine and immune regulation. As a result of these properties, the MSCs have great clinical application prospects, especially in the regeneration of injured tissues, functional reconstruction, and cell therapy. However, the transplanted MSCs are prone to ageing and apoptosis and have a difficult to control direction differentiation. Therefore, it is necessary to effectively regulate the functions of the MSCs to promote their desired effects. In recent years, it has been found that mitochondria, the main organelles responsible for energy metabolism and adenosine triphosphate production in cells, play a key role in regulating different functions of the MSCs through various mechanisms. Thus, mitochondria could act as effective targets for regulating and promoting the functions of the MSCs. In this review, we discuss the research status and current understanding of the role and mechanism of mitochondrial energy metabolism, morphology, transfer modes, and dynamics on MSC functions.

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The Small GTPases Rab27b Regulates Mitochondrial Fatty Acid Oxidative Metabolism of Cardiac Mesenchymal Stem Cells

Cited by 12 publications

References 47 publications

The Impaired Bioenergetics of Diabetic Cardiac Microvascular Endothelial Cells

The Impaired Bioenergetics of Diabetic Cardiac Microvascular Endothelial Cells

High-Fat Diet-Induced Obesity Primes Impaired Fatty Acid β-Oxidation and Consequent Ovarian Dysfunction During Early Pregnancy

The role and mechanism of mitochondrial functions and energy metabolism in the function regulation of the mesenchymal stem cells

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