Dataset Information

Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation.

ABSTRACT: Although mitochondrial fission has been reported to increase proliferative capacity and collagen production, it can also contribute to mitochondrial impairment, which is detrimental to cell survival. The aim of the present study was to investigate the role of mitochondrial fission in cardiac fibroblasts (CF) activation and explore the mechanisms involved in the maintenance of mitochondrial health under this condition. For this, changes in the levels of mitochondrial fission/fusion-related proteins were assessed in transforming growth factor beta 1 (TGF-?1)-activated CF, whereas the role of mitochondrial fission during this process was also elucidated, as were the underlying mechanisms. The interaction between mitochondrial fission and mitophagy, the main defense mechanism against mitochondrial impairment, was also explored. The results showed that the mitochondria in TGF-?1-treated CF were noticeably more fragmented than those of controls. The expression of several mitochondrial fission-related proteins was markedly upregulated, and the levels of fusion-related proteins were also altered, but to a lesser extent. Inhibiting mitochondrial fission resulted in a marked attenuation of TGF-?1-induced CF activation. The TGF-?1-induced increase in glycolysis was greatly suppressed in the presence of a mitochondrial inhibitor, whereas a glycolysis-specific antagonist exerted little additional antifibrotic effects. TGF-?1 treatment increased cellular levels of reactive oxygen species (ROS) and triggered mitophagy, but this effect was reversed following the application of ROS scavengers. For the signals mediating mitophagy, the expression of Pink1, but not Bnip3l/Nix or Fundc1, exhibited the most significant changes, which could be counteracted by treatment with a mitochondrial fission inhibitor. Pink1 knockdown suppressed CF activation and mitochondrial fission, which was accompanied by increased CF apoptosis. In conclusion, mitochondrial fission resulted in increased glycolysis and played a crucial role in CF activation. Moreover, mitochondrial fission promoted reactive oxygen species (ROS) production, leading to mitophagy and the consequent degradation of the impaired mitochondria, thus promoting CF survival and maintaining their activation.

SUBMITTER: Gao QY

PROVIDER: S-EPMC7874126 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation.

Gao Qing-Yuan QY Zhang Hai-Feng HF Tao Jun J Chen Zhi-Teng ZT Liu Chi-Yu CY Liu Wen-Hao WH Wu Mao-Xiong MX Yin Wen-Yao WY Gao Guang-Hao GH Xie Yong Y Yang Ying Y Liu Pin-Ming PM Wang Jing-Feng JF Chen Yang-Xin YX

Frontiers in cell and developmental biology 20210121

Although mitochondrial fission has been reported to increase proliferative capacity and collagen production, it can also contribute to mitochondrial impairment, which is detrimental to cell survival. The aim of the present study was to investigate the role of mitochondrial fission in cardiac fibroblasts (CF) activation and explore the mechanisms involved in the maintenance of mitochondrial health under this condition. For this, changes in the levels of mitochondrial fission/fusion-related protei ...[more]

PMID: 33585469

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Project description:The cardiac microvascular system, which is primarily composed of monolayer endothelial cells, is the site of blood supply and nutrient exchange to cardiomyocytes. However, microvascular ischemia/reperfusion injury (IRI) following percutaneous coronary intervention is a woefully neglected topic, and few strategies are available to reverse such pathologies. Here, we studied the effects of melatonin on microcirculation IRI and elucidated the underlying mechanism. Melatonin markedly reduced infarcted area, improved cardiac function, restored blood flow, and lower microcirculation perfusion defects. Histological analysis showed that cardiac microcirculation endothelial cells (CMEC) in melatonin-treated mice had an unbroken endothelial barrier, increased endothelial nitric oxide synthase expression, unobstructed lumen, reduced inflammatory cell infiltration, and less endothelial damage. In contrast, AMP-activated protein kinase α (AMPKα) deficiency abolished the beneficial effects of melatonin on microvasculature. In vitro, IRI activated dynamin-related protein 1 (Drp1)-dependent mitochondrial fission, which subsequently induced voltage-dependent anion channel 1 (VDAC1) oligomerization, hexokinase 2 (HK2) liberation, mitochondrial permeability transition pore (mPTP) opening, PINK1/Parkin upregulation, and ultimately mitophagy-mediated CMEC death. However, melatonin strengthened CMEC survival via activation of AMPKα, followed by p-Drp1S616 downregulation and p-Drp1S37 upregulation, which blunted Drp1-dependent mitochondrial fission. Suppression of mitochondrial fission by melatonin recovered VDAC1-HK2 interaction that prevented mPTP opening and PINK1/Parkin activation, eventually blocking mitophagy-mediated cellular death. In summary, this study confirmed that melatonin protects cardiac microvasculature against IRI. The underlying mechanism may be attributed to the inhibitory effects of melatonin on mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis via activation of AMPKα.

Project description:Anthracyclines are the critical component in a majority of pediatric chemotherapy regimens due to their broad anticancer efficacy. Unfortunately, the vast majority of long-term childhood cancer survivors will develop a chronic health condition caused by their successful treatments and severe cardiac disease is a common life-threatening outcome that is unequivocally linked to previous anthracycline exposure. The intricacies of how anthracyclines such as doxorubicin, damage the heart and initiate a disease process that progresses over multiple decades is not fully understood. One area left largely unstudied is the role of the cardiac fibroblast, a key cell type in cardiac maturation and injury response. In this study, we demonstrate the effect of doxorubicin on cardiac fibroblast function in the presence and absence of the critical DNA damage response protein p53. In wildtype cardiac fibroblasts, doxorubicin-induced damage correlated with decreased proliferation and migration, cell cycle arrest, and a dilated cardiomyopathy gene expression profile. Interestingly, these doxorubicin-induced changes were completely or partially restored in p53-/- cardiac fibroblasts. Moreover, in wildtype cardiac fibroblasts, doxorubicin produced DNA damage and mitochondrial dysfunction, both of which are well-characterized cell stress responses induced by cytotoxic chemotherapy and varied forms of heart injury. A 3-fold increase in p53 (p = 0.004) prevented the completion of mitophagy (p = 0.032) through sequestration of Parkin. Interactions between p53 and Parkin increased in doxorubicin-treated cardiac fibroblasts (p = 0.0003). Finally, Parkin was unable to localize to the mitochondria in wildtype cardiac fibroblasts, but mitochondrial localization was restored in p53-/- cardiac fibroblasts. These findings strongly suggest that cardiac fibroblasts are an important myocardial cell type that merits further study in the context of doxorubicin treatment. A more robust knowledge of the role cardiac fibroblasts play in the development of doxorubicin-induced cardiotoxicity will lead to novel clinical strategies that will improve the quality of life of cancer survivors.

Dataset Information

Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation.

Publications

Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation.

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