Mitochondrial dysfunction in fibrotic diseases

Li, Xinyu; Zhang, Wei; Cao, Qingtai; Wang, Zeyu; Zhao, Mingyi; Xu, Lei; Zhuang, Quan

doi:10.1038/s41420-020-00316-9

Cited by 107 publications

(67 citation statements)

References 131 publications

(191 reference statements)

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“…Mitophagy is a selective autophagic process for the removal of the damaged mitochondria and is vital for cell survival. Mitophagy has been reported to be activated by profibrotic stimuli and to play a key role in fibroblasts activation and organ fibrosis (Li et al, 2020 ). Consequently, the aim of the current study was to investigate the role of mitochondrial fission in CF activation.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED: Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

Gao

Zhang

Tao

et al. 2021

Front. Cell Dev. Biol.

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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-β1)-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-β1-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-β1-induced CF activation. The TGF-β1-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-β1 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.

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Section: Introductionmentioning

confidence: 99%

RETRACTED: Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

Gao

Zhang

Tao

et al. 2021

Front. Cell Dev. Biol.

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“…Support for this comes from research that indicates that CBD can induce autophagy, which could be important in epilepsy ( Hosseinzadeh et al, 2016 ), alcohol-induced liver damage ( Yang et al, 2019 ), and cancer ( Shrivastava et al, 2011 ). Autophagy is pivotal in maintaining overall mitochondrial health and involves VDAC1 and mTOR; a key trigger of the process is mitochondrial dysfunction ( Li et al, 2020 ). Induction of mitochondrial stress could lead to mitophagy, which in some cells restores homeostasis, for instance, ensuring inflammation resolution, but in others, such as cancer cells, it results in death.…”

Section: Discussionmentioning

confidence: 99%

Cannabidiol Modulates Mitochondrial Redox and Dynamics in MCF7 Cancer Cells: A Study Using Fluorescence Lifetime Imaging Microscopy of NAD(P)H

Mould

Botchway

Parkinson

et al. 2021

Front. Mol. Biosci.

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The cannabinoid, cannabidiol (CBD), is part of the plant's natural defense system that when given to animals has many useful medicinal properties, including activity against cancer cells, modulation of the immune system, and efficacy in epilepsy. Although there is no consensus on its precise mode of action as it affects many cellular targets, CBD does appear to influence mitochondrial function. This would suggest that there is a cross-kingdom ability to modulate stress resistance systems that enhance homeostasis. As NAD(P)H autofluorescence can be used as both a metabolic sensor and mitochondrial imaging modality, we assessed the potential of this technique to study the in vitro effects of CBD using 2-photon excitation and fluorescence lifetime imaging microscopy (2P-FLIM) of NAD(P)H against more traditional markers of mitochondrial morphology and cellular stress in MCF7 breast cancer cells. 2P-FLIM analysis revealed that the addition of CBD induced a dose-dependent decrease in bound NAD(P)H, with 20 µM treatments significantly decreased the contribution of bound NAD(P)H by 14.6% relative to the control (p < 0.001). CBD also increased mitochondrial concentrations of reactive oxygen species (ROS) (160 ± 53 vs. 97.6 ± 4.8%, 20 µM CBD vs. control, respectively, p < 0.001) and Ca2+ (187 ± 78 vs. 105 ± 10%, 20 µM CBD vs. the control, respectively, p < 0.001); this was associated with a significantly decreased mitochondrial branch length and increased fission. These are all suggestive of mitochondrial stress. Our results support the use of NAD(P)H autofluorescence as an investigative tool and provide further evidence that CBD can modulate mitochondrial function and morphology in a dose-dependent manner, with clear evidence of it inducing oxidative stress at higher concentrations. This continues to support emerging data in the literature and may provide further insight into its overall mode of action, not only in cancer, but potentially its function in the plant and why it can act as a medicine.

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“…To test HCQ’s effects on lipid membranes, we first examined the effect of HCQ on the apparent structure (size and number) of GM1 rafts by direct stochastic optical reconstruction microscopy (dSTORM) in the membranes of HEK293T cells using density-based spatial clustering of applications with noise (DBSCAN). We found 50 μM HCQ, a minimum saturating concentration that was shown to inhibit viral entry 3 , increased the number and apparent size (Fig. 2A-C) of GM1 rafts.…”

Section: Resultsmentioning

confidence: 77%

“…Currently, millions of people have been infected with SARS-CoV-2 worldwide. Proposed treatments for severe symptoms include a well-known FDA approved antimalarial agents chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) 3–7 , but their mechanism of action are poorly understood in COVID19 and their proven antiviral effects are largely limited to in vitro studies. A retrospective study claimed a benefit in particular with the macrolide antibiotic azithromycin 8 , but their use is not without controversy 9 10 , and randomized control studies without an antibiotic appeared to have no benefit 11 .…”

Section: Introductionmentioning

confidence: 99%

Hydroxychloroquine: mechanism of action inhibiting SARS-CoV2 entry

Yuan

Pavel

Wang

et al. 2020

Preprint

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Background: SARS-coronavirus 2 (SARS-CoV-2) is currently causing a worldwide pandemic. Potential drugs identified for the treatment of SARS-CoV-2 infection include chloroquine (CQ), its derivative hydroxychloroquine (HCQ), and the anesthetic propofol. Their mechanism of action in SARS-CoV-2 infection is poorly understood. Recently, anesthetics, both general and local, were shown to disrupt ordered lipid domains. These same lipid domains recruit the SARS-CoV-2 surface receptor angiotensin converting enzyme 2 (ACE2) to an endocytic entry point and their disruption by cholesterol depletion decreases ACE2 recruitment and viral entry. Methods: Viral entry was determined using a SARS-CoV-2 pseudovirus (SARS2-PV) and a luciferase reporter gene expressed by the virus after treatment of the cells with 50 micromolar propofol, tetracaine, HCQ, and erythromycin. HCQ disruption of monosialotetrahexosylganglioside1 (GM1) lipid rafts, phosphatidylinositol 4,5-bisphosphate (PIP2) domains, and ACE2 receptor at nanoscale distances was monitored by direct stochastic reconstruction microscopy (dSTORM). Cells were fixed, permeabilized, and then labeled with either fluorescent cholera toxin B (CTxB) or antibody and then fixed again prior to imaging. Cluster analysis of dSTORM images was used to determine size and number and cross pair correlation was used to determine trafficking of endogenously expressed ACE2 in and out of lipid domains. Results: Propofol, tetracaine, and HCQ inhibit SARS2-PV viral entry. HCQ directly perturbs both GM1 lipid rafts and PIP2 domains. GM1 rafts increased in size and number similar to anesthetic disruption of lipid rafts; PIP2 domains decreased in size and number. HCQ blocked both GM1 and PIP2 domains ability to attract and cluster ACE2. Conclusions: We conclude HCQ is an anesthetic-like compound that disrupts GM1 lipid rafts similar to propofol and other local or general anesthetics. Furthermore, we conclude disruption of GM1 raft function, and not the concentration of GM1 raft molecules, governs the antiviral properties of HCQ. HCQ disruption of the membrane appears to also disrupt the production of host defense peptide, hence an antimicrobial such as erythromycin could be an important combined treatment. Nonetheless erythromycin has anti-SARS-CoV-2 activity and may combine with HCQ to reduce infection.

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Mitochondrial dysfunction in fibrotic diseases

Cited by 107 publications

References 131 publications

RETRACTED: Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

RETRACTED: Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

Cannabidiol Modulates Mitochondrial Redox and Dynamics in MCF7 Cancer Cells: A Study Using Fluorescence Lifetime Imaging Microscopy of NAD(P)H

Hydroxychloroquine: mechanism of action inhibiting SARS-CoV2 entry

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