Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications

McLaughlin, Todd; Medina, Andy; Perkins, Jacob; Yera, Maria; Wang, Joshua J.; Zhang, Sarah X.

doi:10.1186/s13024-022-00528-w

Cited by 37 publications

(23 citation statements)

References 219 publications

(248 reference statements)

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“…We established that BAPT-AM (Ca 2+ chelator) reverses hyperglycemia induced-mitochondrial dysfunction and apoptosis via the mPTP-mediated Cyt c/Caspase-3 pathway, suggesting that mitochondrial Ca 2+ overload accelerates the DR process via mitochondrial dysfunction. Dysfunction of the ER and/or the mitochondria plays a signi cant role in DR development [27,51]. The mechanisms of ER-mitochondrial coupling are still unclear.…”

Section: Discussionmentioning

confidence: 99%

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WITHDRAWN: GRP75 modulates endoplasmic reticulum-mitochondria coupling and accelerates Ca 2+ -dependent endothelial cells apoptosis in diabetic retinopathy

Shao

et al. 2022

Preprint

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Background Endoplasmic reticulum (ER) and mitochondrial dysfunction play fundamental roles in the pathogenesis of diabetic retinopathy (DR). The communication between the mitochondria and the ER is mediated by a functional subdomain referred to as the mitochondria-associated membrane (MAM). However, the mechanism underlying material exchange between the ER and mitochondria are poorly understood. This study aimed to explore the role of IP3R1-GRP75-VDAC1 axis in modulating Ca2+ homeostasis in RMECs. Methods In this study, we established high glucose (HG) and advanced glycosylation end products (AGEs)-induced human retinal vascular endothelial cells (RMECs) models in vitro, and streptozotocin (STZ)-induced DR model in vivo. CCK8 assay and Calcein-AM/PI double stain were used to detect cell viability.The ER-Tracker Red Kit and MitoTracker-Green are used to co-localize ER and mitochondria. Mitochondrial Ca2+ was detected using Rhod-2 AM. Co-immunoprecipitation (co-IP) was used to examine the interaction between IP3R1, GRP75 and VDAC1. MitoSOX™ Red Probe, mPTP Assay, and JC-1 Assay are used to measure mitochondrial function. Evans blue dye, retinal PAS staining, and TUNEL assay were used to assess retinal function. Results Our data demonstrated that there was increased ER-mitochondria coupling in the RMECs, which was accompanied by elevated mitochondrial calcium ions (Ca2+) and mitochondrial dysfunction (mitochondrial membrane potential, ΔΨm; and mitochondrial ROS) under HG or AGEs transferred ER Ca2+ into the mitochondria. Elevated mitochondrial Ca2+ concentrations led to an increase in mitochondrial ROS and a decline in mitochondrial membrane potential. These events resulted in mitochondrial dysfunction and elevation of mitochondrial permeability, which induced cytoplasmic Cyt c/Caspase-3-mediated cell apoptosis. The above phenomenon was reversed by BAPTA-AM (an intracellular calcium chelator) and tunicamycin (TUN), a common ERS inducer. In addition, 4-PBA, (an ERS inhibitor), was shown to reverse retinal dysfunction in STZ-induced DR rats. Conclusions Our findings demonstrated that DR fuels the formation of ER-mitochondria coupling via the IP3R1-GRP75-VDAC1 axis, which facilitates transport of Ca2+ from the ER to the mitochondria, eventually leading to mitochondrial dysfunction and apoptosis of endothelial cells. Our results demonstrated that inhibition of ER-mitochondrial coupling, including inhibition of GRP75 or Ca2+ overload, may be a potential therapeutic target in DR.

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Section: Discussionmentioning

confidence: 99%

“…ERS triggers ER-mitochondrial coupling and transfers Ca 2+ into the mitochondria ERS and mitochondrial dysfunction in RMECs are the most evident pathological phenomena in DR [27].…”

Section: Mitochondria Ca 2+ -Induced Mitochondrial Dysfunction and Ap...mentioning

confidence: 99%

WITHDRAWN: GRP75 modulates endoplasmic reticulum-mitochondria coupling and accelerates Ca 2+ -dependent endothelial cells apoptosis in diabetic retinopathy

Shao

et al. 2022

Preprint

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“…ERS and mitochondrial dysfunction in RMECs are the most evident pathological phenomena in DR [ 30 ]. However, the mechanisms underlying ERS and mitochondrial dysfunction in RMECs have not been elucidated.…”

Section: Resultsmentioning

confidence: 99%

“…Dysfunction of the ER and/or the mitochondria plays a significant role in DR development [ 30 , 54 ]. The mechanisms of ER–mitochondrial coupling are still unclear.…”

Section: Discussionmentioning

confidence: 99%

GRP75 Modulates Endoplasmic Reticulum–Mitochondria Coupling and Accelerates Ca2+-Dependent Endothelial Cell Apoptosis in Diabetic Retinopathy

Shao

et al. 2022

Biomolecules

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Endoplasmic reticulum (ER) and mitochondrial dysfunction play fundamental roles in the pathogenesis of diabetic retinopathy (DR). However, the interrelationship between the ER and mitochondria are poorly understood in DR. Here, we established high glucose (HG) or advanced glycosylation end products (AGE)-induced human retinal vascular endothelial cell (RMEC) models in vitro, as well as a streptozotocin (STZ)-induced DR rat model in vivo. Our data demonstrated that there was increased ER–mitochondria coupling in the RMECs, which was accompanied by elevated mitochondrial calcium ions (Ca2+) and mitochondrial dysfunction under HG or AGE incubation. Mechanistically, ER–mitochondria coupling was increased through activation of the IP3R1–GRP75–VDAC1 axis, which transferred Ca2+ from the ER to the mitochondria. Elevated mitochondrial Ca2+ led to an increase in mitochondrial ROS and a decline in mitochondrial membrane potential. These events resulted in the elevation of mitochondrial permeability and induced the release of cytochrome c from the mitochondria into the cytoplasm, which further activated caspase-3 and promoted apoptosis. The above phenomenon was also observed in tunicamycin (TUN, ER stress inducer)-treated cells. Meanwhile, BAPTA-AM (calcium chelator) rescued mitochondrial dysfunction and apoptosis in DR, which further confirmed of our suspicions. In addition, 4-phenylbutyric acid (4-PBA), an ER stress inhibitor, was shown to reverse retinal dysfunction in STZ-induced DR rats in vivo. Taken together, our findings demonstrated that DR fueled the formation of ER–mitochondria coupling via the IP3R1–GRP75–VDAC1 axis and accelerated Ca2+-dependent cell apoptosis. Our results demonstrated that inhibition of ER–mitochondrial coupling, including inhibition of GRP75 or Ca2+ overload, may be a potential therapeutic target in DR.

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“…(29,33) Further, dysregulated signaling through all three UPR pathways is associated with retinal degeneration in diseases such as retinitis pigmentosa. (32)(33)(34)(35) This suggests that the retina, and specifically photoreceptor cells within the retina, are highly sensitive to imbalances in UPR signaling.…”

Section: Introductionmentioning

confidence: 99%

Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

Rosarda

Giles

Harkins‐Perry

et al. 2022

Preprint

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1-Deoxysphingolipids (1-dSLs) are atypical cytotoxic sphingolipids formed through the substitution of alanine for serine in de novo sphingolipid biosynthesis. Accumulation of 1-dSLs has been linked to diseases of the eye such as diabetic retinopathy and Macular Telangiectasia Type 2 (MacTel). However, the molecular mechanisms by which 1-dSLs induce toxicity in retinal cells remains poorly understood. Here, we integrate bulk and single-nucleus RNA-sequencing to define the biological pathways that contribute to toxicity caused by the 1-dSL species, 1-deoxysphinganine (1-dSA), in human retinal organoids. Our results demonstrate that 1-dSA preferentially and differentially activates signaling arms of the unfolded protein response (UPR) in photoreceptor cells and Muller glia within retinal organoids. Using a combination of pharmacologic inhibitors and activators, we define the roles for individual arms of the UPR in 1-dSL-mediated toxicity. We show that sustained PERK signaling through the integrated stress response (ISR) promotes 1-dSL-induced apoptosis in photoreceptors. In contrast, deficiencies in signaling through the ATF6 arm of the UPR contribute to photoreceptor toxicity. These results indicate that imbalanced signaling between the pro-apoptotic PERK/ISR and protective ATF6 arms of the UPR contributes to 1-dSL-induced photoreceptor toxicity. Further, our results identify new opportunities to intervene in 1-dSL linked diseases through targeting different signaling arms of the UPR.

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Cellular stress signaling and the unfolded protein response in retinal degeneration: mechanisms and therapeutic implications

Cited by 37 publications

References 219 publications

WITHDRAWN: GRP75 modulates endoplasmic reticulum-mitochondria coupling and accelerates Ca 2+ -dependent endothelial cells apoptosis in diabetic retinopathy

WITHDRAWN: GRP75 modulates endoplasmic reticulum-mitochondria coupling and accelerates Ca 2+ -dependent endothelial cells apoptosis in diabetic retinopathy

GRP75 Modulates Endoplasmic Reticulum–Mitochondria Coupling and Accelerates Ca2+-Dependent Endothelial Cell Apoptosis in Diabetic Retinopathy

Imbalanced Unfolded Protein Response Signaling Contributes to 1-Deoxysphingolipid Retinal Toxicity

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