The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson’s Disease

Ren, Haigang; Zhai, Wei; Lu, Xiaojun; Wang, Guanghui

doi:10.3389/fnagi.2021.691881

Cited by 58 publications

(42 citation statements)

References 208 publications

(255 reference statements)

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“…Accordingly, targeting this pathway may have a therapeutic potential to reduce renal fibrosis and apoptosis in kidney diseases. Also, ER stress may release Ca 2+ from ER to activate CaMKKβ/AMPK, inhibit mTORC1, or activate death-associated protein kinase 1 for autophagy [ 41 ]. Whether these mechanisms contribute to autophagy activation by ER stress in renal fibrosis remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis

et al. 2021

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Both endoplasmic reticulum (ER) stress and autophagy have been implicated in chronic kidney injury and renal fibrosis. However, the relationship and regulatory mechanisms between ER stress and autophagy under this condition remain largely unknown. In this study, we first established a mouse model of ER stress-induced chronic kidney injury by 2 weekly injections of a low dose of tunicamycin (TM), a classical ER stress inducer. This model showed the induction of ER stress, autophagy, fibrosis and apoptosis in kidney tissues. In vitro, TM also induced ER stress, autophagy, fibrosis and apoptosis in HK-2 human kidney proximal tubular cells and BUMPT-306 mouse kidney proximal tubular cells. In these cells, autophagy inhibitor suppressed TM-induced fibrotic changes and apoptosis, suggesting an involvement of autophagy in ER stress-associated chronic kidney injury. PERK inhibitor ameliorated autophagy, fibrotic protein expression and apoptosis in TM-treated cells, indicating a role of the PERK/eIF2α pathway in autophagy activation during ER stress. Similar results were shown in TGF-β1-treated HK-2 cells. Interestingly, in both TM- or TGF-β1-treated kidney proximal tubular cells, inhibition of autophagy exaggerated ER stress, suggesting that autophagy induced by ER stress provides a negative feedback mechanism to reduce the stress. Together, these results unveil a reciprocal regulation between ER stress and autophagy in chronic kidney injury and fibrosis.

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Section: Discussionmentioning

confidence: 99%

Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis

et al. 2021

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“…ERO1A is a FAD-dependent protein, which reoxidizes protein disulfide isomerases (such as PDIA1) and produces ROS (hydrogen peroxide), being involved in endoplasmic reticulum stress [ 44 , 52 ]. In its turn, endoplasmic reticulum stress is a component of neurodegenerative diseases, linked to autophagy [ 53 ] and perturbed calcium exchange between endoplasmic reticulum and mitochondria [ 54 ]. Inhibiting the ERO1A pathway by either pharmacological or genetic means [ 45 , 46 ] reduces ROS production upon endoplasmic reticulum stress.…”

Section: Discussionmentioning

confidence: 99%

Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293

Aleshin

Artiukhov

Kaehne

et al. 2021

IJMS

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Coupling glycolysis and mitochondrial tricarboxylic acid cycle, pyruvate dehydrogenase (PDH) complex (PDHC) is highly responsive to cellular demands through multiple mechanisms, including PDH phosphorylation. PDHC also produces acetyl-CoA for protein acetylation involved in circadian regulation of metabolism. Thiamine (vitamin B1) diphosphate (ThDP) is known to activate PDH as both coenzyme and inhibitor of the PDH inactivating kinases. Molecular mechanisms integrating the function of thiamine-dependent PDHC into general redox metabolism, underlie physiological fitness of a cell or an organism. Here, we characterize the daytime- and thiamine-dependent changes in the rat brain PDHC function, expression and phosphorylation, assessing their impact on protein acetylation and metabolic regulation. Morning administration of thiamine significantly downregulates both the PDH phosphorylation at Ser293 and SIRT3 protein level, the effects not observed upon the evening administration. This action of thiamine nullifies the daytime-dependent changes in the brain PDHC activity and mitochondrial acetylation, inducing diurnal difference in the cytosolic acetylation and acetylation of total brain proteins. Screening the daytime dependence of central metabolic enzymes and proteins of thiol/disulfide metabolism reveals that thiamine also cancels daily changes in the malate dehydrogenase activity, opposite to those of the PDHC activity. Correlation analysis indicates that thiamine abrogates the strong positive correlation between the total acetylation of the brain proteins and PDHC function. Simultaneously, thiamine heightens interplay between the expression of PDHC components and total acetylation or SIRT2 protein level. These thiamine effects on the brain acetylation system change metabolic impact of acetylation. The changes are exemplified by the thiamine enhancement of the SIRT2 correlations with metabolic enzymes and proteins of thiol-disulfide metabolism. Thus, we show the daytime- and thiamine-dependent changes in the function and phosphorylation of brain PDHC, contributing to regulation of the brain acetylation system and redox metabolism. The daytime-dependent action of thiamine on PDHC and SIRT3 may be of therapeutic significance in correcting perturbed diurnal regulation.

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“…These findings collectively imply that ER stress-autophagy induction-inflammasome activation axis critically contributes to cytotoxic effects of leptin in hepatocytes. ER stress induces autophagy activation via multiple mechanisms, such as through the transcriptional up-regulation of the genes that are related to autophagy [32], the suppression of mTOR activity [33], and the dissociation of Bcl-2 and Beclin-1, which results in the generation of free Beclin-1 [34]. At this stage, we could not clearly understand the molecular interactions comprising ER stress, autophagy induction, and inflammasome activation.…”

Section: Discussionmentioning

confidence: 97%

Leptin Induces Apoptotic and Pyroptotic Cell Death via NLRP3 Inflammasome Activation in Rat Hepatocytes

Baral

2021

IJMS

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Leptin, a hormone that is predominantly produced by adipose tissue, is closely associated with various liver diseases. However, there is a lack of understanding as to whether leptin directly induces cytotoxic effects in hepatocytes as well as the mechanisms that are involved. Inflammasomes, which are critical components in the innate immune system, have been recently shown to modulate cell death. In this study, we examined the effect of leptin on the viability of rat hepatocytes and the underlying mechanisms, with a particular focus on the role of inflammasomes activation. Leptin treatment induced cytotoxicity in rat hepatocytes, as determined by decreased cell viability, increased caspase-3 activity, and the enhanced release of lactate dehydrogenase. NLRP3 inflammasomes were activated by leptin both in vitro and in vivo, as determined by the maturation of interleukin-1β and caspase-1, and the increased expression of inflammasome components, including NLRP3 and ASC. Mechanistically, leptin-induced inflammasome activation is mediated via the axis of ROS production, ER stress, and autophagy. Notably, the inhibition of inflammasomes by treatment with the NLRP3 inhibitor or the IL-1 receptor antagonist protected the hepatocytes from leptin-induced cell death. Together, these results indicate that leptin exerts cytotoxic effects in hepatocytes, at least in part, via the activation of NLRP3 inflammasomes.

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The Cross-Links of Endoplasmic Reticulum Stress, Autophagy, and Neurodegeneration in Parkinson’s Disease

Cited by 58 publications

References 208 publications

Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis

Reciprocal regulation between ER stress and autophagy in renal tubular fibrosis and apoptosis

Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293

Leptin Induces Apoptotic and Pyroptotic Cell Death via NLRP3 Inflammasome Activation in Rat Hepatocytes

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