CaMK II -induced Drp1 phosphorylation contributes to blue light-induced AIF-mediated necroptosis in retinal R28 cells

Yang, Dawei; Rong, Rong; Yang, Rongliang; You, Mengling; Wang, Mengxiao; Li, Haibo; Ji, Dan

doi:10.1016/j.bbrc.2021.04.082

Cited by 19 publications

(12 citation statements)

References 34 publications

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“…Additionally, GSK872 and Nec-1 can rescue RGCs from glutamate-induced necroptosis, demonstrating neuroprotective effects. However, in addition to the classical pathway, there are other mechanisms regulating necroptosis such as the apoptosis-inducing factor (AIF) dependent pathway [55][56][57]. It is worth further study to investigate whether other pathways and molecules contribute to glutamate-triggered necroptosis of RGCs.…”

Section: Discussionmentioning

confidence: 99%

GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma

Liu

Yang

et al. 2022

J Neuroinflammation

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Background Glaucoma, the major cause of irreversible blindness worldwide, is characterized by progressive degeneration of retinal ganglion cells (RGCs). Current treatments for glaucoma only slow or partially prevent the disease progression, failing to prevent RGCs death and visual field defects completely. Glutamate excitotoxicity via N-methyl-d-aspartic acid (NMDA) receptors plays a vital role in RGCs death in glaucoma, which is often accompanied by oxidative stress and NLRP3 inflammasome activation. However, the exact mechanisms remain unclear. Methods The glutamate-induced R28 cell excitotoxicity model and NMDA-induced mouse glaucoma model were established in this study. Cell counting kit-8, Hoechst 33342/PI dual staining and lactate dehydrogenase release assay were performed to evaluate cell viability. Annexin V-FITC/PI double staining was used to detect apoptosis and necrosis rate. Reactive oxygen species (ROS) and glutathione (GSH) were used to detect oxidative stress in R28 cells. Levels of proinflammatory cytokines were measured by qRT-PCR. Transmission electron microscopy (TEM) was used to detect necroptotic morphological changes in RGCs. Retinal RGCs numbers were detected by immunofluorescence. Hematoxylin and eosin staining was used to detect retinal morphological changes. The expression levels of RIP1, RIP3, MLKL and NLRP3 inflammasome-related proteins were measured by immunofluorescence and western blotting. Results We found that glutamate excitotoxicity induced necroptosis in RGCs through activation of the RIP1/RIP3/MLKL pathway in vivo and in vitro. Administration of the RIP3 inhibitor GSK872 and RIP1 inhibitor necrostatin-1 (Nec-1) prevented glutamate-induced RGCs loss, retinal damage, neuroinflammation, overproduction of ROS and a decrease in GSH. Furthermore, after suppression of the RIP1/RIP3/MLKL pathway by GSK872 and Nec-1, glutamate-induced upregulation of key proteins involved in NLRP3 inflammasome activation, including NLRP3, pro-caspase-1, cleaved-caspase-1, and interleukin-1β (IL-1β), was markedly inhibited. Conclusions Our findings suggest that the RIP1/RIP3/MLKL pathway mediates necroptosis of RGCs and regulates NLRP3 inflammasome activation induced by glutamate excitotoxicity. Moreover, GSK872 and Nec-1 can protect RGCs from necroptosis and suppress NLRP3 inflammasome activation through inhibition of RIP1/RIP3/MLKL pathway, conferring a novel neuroprotective treatment for glaucoma.

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Section: Discussionmentioning

confidence: 99%

GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma

Liu

Yang

et al. 2022

J Neuroinflammation

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“…To elucidate the mechanism by which RCAN1 de ciency leads to Drp1 phosphorylation, we focused on Calcium/calmodulin-dependent protein kinase II (CaMKII). Previous studies identi ed CaMKII as a modulator of mitochondrial Ca2 + homeostasis and inhibition of CaMKII suppressed mitochondrial Ca2 + uniporter (MCU) and mPTP opening [14,15], which partly due to the regulation of Drp1 activity [16,17]. Therefore, we determined the CaMKII activity in isolated adult mouse cardiomyocytes after stimulating by LPS for 24 hours.…”

Section: Rcan1 Suppressed Drp1 Phosphorylation and Preserved Mitochon...mentioning

confidence: 99%

RCAN1 deficiency aggravates sepsis-induced cardiac remodeling and dysfunction through accelerating mitochondrial pathological fission

Zhuang

Chen

et al. 2022

Preprint

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Background Cardiac dysfunction and remodeling are serious complications of sepsis and are correlated with high mortality. RCAN1 is a feedback regulator of cardiac hypertrophy. Here we aim to investigate role of RCAN1 in septic cardiomyopathy. Methods RCAN1-/- mice and WT mice were randomly divided into control and LPS-induced groups, some with Midiv-1 or KN93 treatment. The protein levels of RCAN1, p-ERK1/2, NFAT3, Drp1, p-Drp1, p-CaMKII in cardiac tissue or cultured cardiomyocytes were detected by Western blotting. Myocardial function was assessed by echocardiography. Cardiac hypertrophy and fibrosis were detected by H&E and Masson's trichrome staining. Mitochondrial morphology was examined by transmission electron microscope. Serum level of LDH was detected by ELISA. Results Our data showed that RCAN1 was downregulated in septic mouse heart and LPS-induced cardiomyocytes, and RCAN1-/- mice had impaired cardiac function and severe myocardial hypertrophy and fibrosis. NFAT3 and p-ERK1/2 were significantly increased in heart tissue of RCAN1-/- mice. Further, RCAN1 deficiency aggravated sepsis-induced cardiac mitochondrial injury as indicated by increased ROS production, pathological fission and the loss of mitochondrial membrane potential. Inhibition of fission by Mdivi-1 reversed LPS-induced cardiac hypertrophy, fibrosis and dysfunction in RCAN1-/- mice. Moreover, RCAN1 depletion caused mitochondrial translocation of CaMKII, which promoted fission and septic hypertrophy. Inhibition of CaMKII with KN93 reduced excessive fission, improved LPS-induced cardiac remodeling and dysfunction in RCAN1-/- mice. Conclusions Our finding demonstrated that RCAN1 deficiency aggravated mitochondrial injury and septic cardiomyopathy through activating CaMKII. RCAN1 serves as a novel therapeutic target for treatment of sepsis-related cardiac remodeling and dysfunction.

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“…The pharmacological or genetic inhibition of RIPK1, RIPK3, or MLKL can block programmed necrosis. Yang showed that blue light exposure (450 nm, 300 lux) caused a caspase-independent death in R28 cells (a retinal neuron), and the application of a specific blocker of necroptosis pathway, necrostatin-1, may markedly attenuate cell death induced by blue light exposure, indicating the necroptosis pathway involves the blue light-induced death of retinal neurons [ 109 ]. Jaadane et al demonstrated that in Wistar rats with retinal light injury induced by four different wavelengths of blue light (507, 473, 467, and 449 nm) exposure, the caspase-independent apoptosis and activation of necroptosis were observed in photoreceptors.…”

Section: The Death Pathways Of Photoreceptorsmentioning

confidence: 99%

The Molecular Mechanism of Retina Light Injury Focusing on Damage from Short Wavelength Light

Fan

Zhang

Chi

et al. 2022

Oxidative Medicine and Cellular Longevity

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Natural visible light is an electromagnetic wave composed of a spectrum of monochromatic wavelengths, each with a characteristic color. Photons are the basic units of light, and their wavelength correlates to the energy of light; short-wavelength photons carry high energy. The retina is a fragile neuronal tissue that senses light and generates visual signals conducted to the brain. However, excessive and intensive light exposure will cause retinal light damage. Within the visible spectrum, short-wavelength light, such as blue light, carries higher energy, and thus the retinal injury, is more significant when exposed to these wavelengths. The damage mechanism triggered by different short-wavelength light varies due to photons carrying different energy and being absorbed by different photosensitive molecules in the retinal neurons. However, photooxidation might be a common molecular step to initiate cell death. Herein, we summarize the historical understanding of light, the key molecular steps related to retinal light injury, and the death pathways of photoreceptors to further decipher the molecular mechanism of retinal light injury and explore potential neuroprotective strategies.

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CaMK II -induced Drp1 phosphorylation contributes to blue light-induced AIF-mediated necroptosis in retinal R28 cells

Cited by 19 publications

References 34 publications

GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma

GSK872 and necrostatin-1 protect retinal ganglion cells against necroptosis through inhibition of RIP1/RIP3/MLKL pathway in glutamate-induced retinal excitotoxic model of glaucoma

RCAN1 deficiency aggravates sepsis-induced cardiac remodeling and dysfunction through accelerating mitochondrial pathological fission

The Molecular Mechanism of Retina Light Injury Focusing on Damage from Short Wavelength Light

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