bims-noxint 2020-10-04 papers

Issue of 2020–10–04
four papers selected by
Laia Caja Puigsubira, Uppsala University

EMBO J. 2020 Oct 01. 39(19): e103530

Nox4 regulates InsP3 receptor-dependent Ca2+ release into mitochondria to promote cell survival.

Matteo Beretta, Celio Xc Santos, Chris Molenaar, Anne D Hafstad, Chris Cj Miller, Aram Revazian, Kai Betteridge, Katrin Schröder, Katrin Streckfuß-Bömeke, James H Doroshow, Roland A Fleck, Tsung-Ping Su, Vsevolod V Belousov, Maddy Parsons, Ajay M Shah.

Cells subjected to environmental stresses undergo regulated cell death (RCD) when homeostatic programs fail to maintain viability. A major mechanism of RCD is the excessive calcium loading of mitochondria and consequent triggering of the mitochondrial permeability transition (mPT), which is especially important in post-mitotic cells such as cardiomyocytes and neurons. Here, we show that stress-induced upregulation of the ROS-generating protein Nox4 at the ER-mitochondria contact sites (MAMs) is a pro-survival mechanism that inhibits calcium transfer through InsP3 receptors (InsP3 R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt-dependent phosphorylation of InsP3 R, thereby inhibiting calcium flux and mPT-dependent necrosis. In hearts subjected to ischemia-reperfusion, Nox4 limits infarct size through this mechanism. These results uncover a hitherto unrecognized stress pathway, whereby a ROS-generating protein mediates pro-survival effects through spatially confined signaling at the MAM to regulate ER to mitochondria calcium flux and triggering of the mPT.

Keywords: InsP3 receptor; NADPH oxidase-4; calcium signaling; cell death; mitochondria-associated membrane

DOI: https://doi.org/10.15252/embj.2019103530

Redox Biol. 2020 Sep 18. pii: S2213-2317(20)30935-6. [Epub ahead of print]37 101730

Rapid, redox-mediated mechanical susceptibility of the cortical microtubule lattice in skeletal muscle.

D'anna M Nelson, Elizabeth K Fasbender, Margurite C Jakubiak, Angus Lindsay, Dawn A Lowe, James M Ervasti.

The highly ordered cortical microtubule lattice of skeletal muscle is disorganized in dystrophin-deficient mdx mice. Implicated mechanisms include loss of dystrophin binding, altered α-tubulin posttranslational modification, expression of a β-tubulin involved in regeneration, and reactive oxygen species (ROS). Here we show that the transverse microtubules in mdx muscle expressing miniaturized dystrophins are rapidly lost after eccentric contraction. Analysis of mdx lines expressing different dystrophin constructs demonstrate that spectrin-like repeats R4-15 and R20-23 were required for mechanically stable microtubules. Microtubule loss was prevented by the non-specific antioxidant N-acetylcysteine while inhibition of NADPH oxidase 2 had only a partial effect, suggesting that ROS from multiple sources mediate the rapid loss of transverse microtubules after eccentric contraction. Finally, ablation of α-dystrobrevin, β- or γ-cytoplasmic actin phenocopied the transverse microtubule instability of miniaturized dystrophins. Our data demonstrate that multiple dystrophin domains, α-dystrobrevin and cytoplasmic actins are necessary for mechanically stable microtubules.

Keywords: Cytoplasmic actin; Duchenne muscular dystrophy; Micro-dystrophin; Microtubules; NADPH oxidase; NOX2; Skeletal muscle; mdx; nNOS

DOI: https://doi.org/10.1016/j.redox.2020.101730

Sci Rep. 2020 Sep 29. 10(1): 16005

Asymmetric dimethylarginine (ADMA) accelerates renal cell fibrosis under high glucose condition through NOX4/ROS/ERK signaling pathway.

Isaivani Jayachandran, Saravanakumar Sundararajan, Saravanakumar Venkatesan, Sairaj Paadukaana, Muthuswamy Balasubramanyam, Viswanathan Mohan, Nagaraj Manickam.

We previously reported that the circulatory level of Asymmetric dimethylarginine (ADMA), an endogenous competitive inhibitor of nitric oxide synthase, was increased in diabetic kidney disease patients. However, the mechanism and the role of ADMA in diabetic kidney injury remain unclear. Hence, our principal aim is to investigate the causal role of ADMA in the progression of renal cell fibrosis under high glucose (HG) treatment and to delineate its signaling alterations in kidney cell injury. High Glucose/ADMA significantly increased fibrotic events including cell migration, invasion and proliferation along with fibrotic markers in the renal cells; whereas ADMA inhibition reversed the renal cell fibrosis. To delineate the central role of ADMA induced fibrotic signaling pathway and its downstream signaling, we analysed the expression levels of fibrotic markers, NOX4, ROS and ERK activity by using specific inhibitors and genetic manipulation techniques. ADMA stimulated the ROS generation along with a significant increase in NOX4 and ERK activity. Further, we observed that ADMA activated NOX-4 and ERK are involved in the extracellular matrix proteins accumulation. Also, we observed that ADMA induced ERK1/2 phosphorylation was decreased after NOX4 silencing. Our study mechanistically demonstrates that ADMA is involved in the progression of kidney cell injury under high glucose condition by targeting coordinated complex mechanisms involving the NOX4- ROS-ERK pathway.

DOI: https://doi.org/10.1038/s41598-020-72943-2

Mol Med Rep. 2020 Nov;22(5): 4151-4162

Protective effects of valsartan administration on doxorubicin‑induced myocardial injury in rats and the role of oxidative stress and NOX2/NOX4 signaling.

Dong Cheng, Libo Chen, Wencheng Tu, Haoren Wang, Qinfu Wang, Lili Meng, Zhu Li, Qin Yu.

Clinical application of doxorubicin (DOX) is hampered by its potential cardiotoxicity, however angiotensin receptor blockers could attenuate DOX‑induced cardiomyopathy. The present study tested the hypothesis that simultaneous administration of valsartan (Val) with DOX could prevent DOX‑induced myocardial injury by modulating myocardial NAD(P)H oxidase (NOX) expression in rats. Eight‑week‑old male Sprague‑Dawley rats were randomly divided into control (CON), DOX, and DOX+Val groups. After 10 weeks, surviving rats underwent echocardiography examination, myocardial mRNA and protein expression detection of NOX1, NOX2 and NOX4. H9C2 cells were used to perform in vitro experiments, reactive oxygen species (ROS) production and apoptosis were observed under the conditions of down‑ or upregulation of NOX2 and NOX4 in DOX‑ and DOX+Val‑treated H9C2 cells. Cardiac function was significantly improved, pathological lesion and collagen volume fraction were significantly reduced in the DOX+Val group compared with the DOX group (all P<0.05). Myocardial protein and mRNA expression of NOX2 and NOX4 was significantly downregulated in DOX+Val group compared with in the DOX group (all P<0.05). In vitro, ROS production and apoptosis in DOX‑treated H9C2 cells was significantly reduced by NOX2‑small interfering (si)RNA and NOX4‑siRNA, and significantly increased by overexpressing NOX2 and NOX4. To conclude, Val applied simultaneously with DOX could prevent DOX‑induced myocardial injury and reduce oxidative stress by downregulating the myocardial expression of NOX2 and NOX4 in rats.

DOI: https://doi.org/10.3892/mmr.2020.11521