scholarly journals Mitochondrial Fission and Mitophagy Reciprocally Orchestrate Cardiac Fibroblasts Activation

2021 ◽  
Vol 8 ◽  
Author(s):  
Qing-Yuan Gao ◽  
Hai-Feng Zhang ◽  
Jun Tao ◽  
Zhi-Teng Chen ◽  
Chi-Yu Liu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Mitochondrial Fission ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Mitochondrial Impairment ◽  
Related Proteins ◽  
Tgf Β1

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.

scholarly journals GPCR transactivation signalling in vascular smooth muscle cells: role of NADPH oxidases and reactive oxygen species

2019 ◽  
Vol 1 (1) ◽  
pp. R1-R11 ◽  
Author(s):  
Raafat Mohamed ◽  
Reearna Janke ◽  
Wanru Guo ◽  
Yingnan Cao ◽  
Ying Zhou ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Growth Factor ◽  
Drug Targets ◽  
Protein Tyrosine Kinase ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Reactive Oxygen ◽  
Transforming Growth Factor Β ◽  
Oxygen Species

The discovery and extension of G-protein-coupled receptor (GPCR) transactivation-dependent signalling has enormously broadened the GPCR signalling paradigm. GPCRs can transactivate protein tyrosine kinase receptors (PTKRs) and serine/threonine kinase receptors (S/TKRs), notably the epidermal growth factor receptor (EGFR) and transforming growth factor-β type 1 receptor (TGFBR1), respectively. Initial comprehensive mechanistic studies suggest that these two transactivation pathways are distinct. Currently, there is a focus on GPCR inhibitors as drug targets, and they have proven to be efficacious in vascular diseases. With the broadening of GPCR transactivation signalling, it is therefore important from a therapeutic perspective to find a common transactivation pathway of EGFR and TGFBR1 that can be targeted to inhibit complex pathologies activated by the combined action of these receptors. Reactive oxygen species (ROS) are highly reactive molecules and they act as second messengers, thus modulating cellular signal transduction pathways. ROS are involved in different mechanisms of GPCR transactivation of EGFR. However, the role of ROS in GPCR transactivation of TGFBR1 has not yet been studied. In this review, we will discuss the involvement of ROS in GPCR transactivation-dependent signalling.

scholarly journals TGF-β1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway

2013 ◽  
Vol 305 (10) ◽  
pp. F1477-F1490 ◽  
Author(s):  
Yoshifusa Abe ◽  
Toru Sakairi ◽  
Craig Beeson ◽  
Jeffrey B. Kopp
Keyword(s):  
Reactive Oxygen Species ◽  
Oxygen Consumption ◽  
Transforming Growth Factor ◽  
Reactive Oxygen ◽  
Mtor Pathway ◽  
Oxygen Species ◽  
Podocyte Injury ◽  
Mitochondrial Dna Copy Number ◽  
Atp Generation ◽  
Tgf Β1

Transforming growth factor (TGF)-β has been associated with podocyte injury; we have examined its effect on podocyte bioenergetics. We studied transformed mouse podocytes, exposed to TGF-β1, using a label-free assay system, Seahorse XF24, which measures oxygen consumption rates (OCR) and extracellular acidification rates (ECAR). Both basal OCR and ATP generation-coupled OCR were significantly higher in podocytes exposed to 0.3–10 ng/ml of TGF-β1 for 24, 48, and 72 h. TGF-β1 (3 ng/ml) increased oxidative capacity 75%, and 96% relative to control after 48 and 72 h, respectively. ATP content was increased 19% and 30% relative to control after a 48- and 72-h exposure, respectively. Under conditions of maximal mitochondrial function, TGF-β1 increased palmitate-driven OCR by 49%. Thus, TGF-β1 increases mitochondrial oxygen consumption and ATP generation in the presence of diverse energy substrates. TGF-β1 did not increase cell number or mitochondrial DNA copy number but did increase mitochondrial membrane potential (MMP), which could explain the OCR increase. Reactive oxygen species (ROS) increased by 32% after TGF-β1 exposure for 48 h. TGF-β activated the mammalian target of rapamycin (mTOR) pathway, and rapamycin reduced the TGF-β1-stimulated increases in OCR, ECAR, ATP generation, cellular metabolic activity, and protein generation. Our data suggest that TGF-β1, acting, in part, via mTOR, increases mitochondrial MMP and OCR, resulting in increased ROS generation and that this may contribute to podocyte injury.

scholarly journals Melatonin Prevents Transforming Growth Factor-β1-Stimulated Transdifferentiation of Renal Interstitial Fibroblasts to Myofibroblasts by Suppressing Reactive Oxygen Species-Dependent Mechanisms

Antioxidants ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 39 ◽  
Author(s):  
Jung-Yeon Kim ◽  
Jae-Hyung Park ◽  
Eon Ju Jeon ◽  
Jaechan Leem ◽  
Kwan-Kyu Park
Keyword(s):  
Reactive Oxygen Species ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Reactive Oxygen ◽  
Transforming Growth Factor Β1 ◽  
Membrane Receptors ◽  
Oxygen Species ◽  
Protective Effects ◽  
Independent Manner ◽  
Tgf Β1

Accumulating evidence suggests that the pineal hormone melatonin displays protective effects against renal fibrosis, but the mechanisms remain poorly understood. Here, we investigate the effect of the pineal hormone on transdifferentiation of renal fibroblasts to myofibroblasts invoked by transforming growth factor-β1 (TGF-β1). Increased proliferation and activation of renal interstitial fibroblasts after TGF-β1 treatment were attenuated by melatonin pretreatment. Mechanistically, melatonin suppressed Smad2/3 phosphorylation and nuclear co-localization of their phosphorylated forms and Smad4 after TGF-β1 stimulation. In addition, increased phosphorylations of Akt, extracellular signal-regulated kinase 1/2, and p38 after TGF-β1 treatment were also suppressed by the hormone. These effects of melatonin were not affected by pharmacological and genetic inhibition of its membrane receptors. Furthermore, melatonin significantly reversed an increase of intracellular reactive oxygen species (ROS) and malondialdehyde levels, and a decrease of the reduced glutathione/oxidized glutathione ratio after TGF-β1 treatment. Finally, TGF-β1-induced proliferation and activation were also suppressed by N-acetylcysteine. Altogether, these findings suggest that the pineal hormone melatonin prevents TGF-β1-induced transdifferentiation of renal interstitial fibroblasts to myofibroblasts via inhibition of Smad and non-Smad signaling cadcades by inhibiting ROS-mediated mechanisms in its receptor-independent manner.

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