The ER-mitochondria interface, where Ca2+ and cell death meet

Ridder, Ian de; Kerkhofs, Martijn; Lemos, Fernanda O.; Loncke, Jens; Bultynck, Geert; Parys, Jan B.

doi:10.1016/j.ceca.2023.102743

Cited by 25 publications

(8 citation statements)

References 285 publications

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“…In addition, ER stress pathway genes such as EIF2S1 and ATF4 [26], and mitochondrial stress pathway genes such as MCU , CASP3, and CASP9 tended to be upregulated in the PSEN1 A246E compared to the WT neurons. In contrast, the VDAC1 encoding the voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane tended to be downregulated in the PSEN1 A246E [37]. Although these changes are not statistically significant (FDR > 0.05), it suggests that Ca 2+ -overload due to the abnormal Ca 2+ -bursts may damages cytosolic organelles, leading to neural malfunctions.…”

Section: Discussionmentioning

confidence: 99%

Carvedilol suppresses ryanodine receptor-dependent Ca²⁺bursts in human neurons bearingPSEN1variants found in early onset Alzheimer’s disease

Hori,

Ai,

Hato

et al. 2023

Preprint

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Seizures are increasingly being recognized as the hallmark of Alzheimer′s disease (AD). Neuronal hyperactivity can be a consequence of neuronal damage caused by abnormal amyloid Aβ depositions. However, it can also be a cell-autonomous phenomenon causing AD by Aβ-independent mechanisms. Indeed, various studies using animal models showed that Ca2+ releases from the endoplasmic reticulum (ER) via type 1 inositol triphosphate receptors (InsP3R1s) and ryanodine receptors (RyRs). To investigate which is the main pathophysiological mechanism in human neurons, we measured Ca2+ signaling in neural cells derived from three early-onset AD patients harboring variants of Presenilin-1 (PSEN1 p.A246E, p.L286V, and p.M146L). Of these, it has been reported that PSEN1 p.A246E and p.L286V did not produce a significant amount of abnormal Aβ. We found that all PSEN1-mutant neurons, but not wild-type, caused abnormal Ca2+-bursts in a manner dependent on the calcium channel, Ryanodine Receptor 2 (RyR2). Indeed, carvedilol, anRyR2 inhibitor, and VK-II-86, an analog of carvedilol without the β-blocking effects, sufficiently eliminated the abnormal Ca2+ bursts. In contrast, Dantrolene, a RyR1 inhibitor, and Xestospongin c, an IP3R inhibitor, did not attenuate the Ca2+-bursts. The RNA-Seq data revealed that ER-stress responsive genes were increased, and mitochondrial Ca2+-transporter genes were decreased in PSEN1A246E cells compared to the WT neurons. Thus, we propose that aberrant Ca2+ signaling is a key link between human pathogenic PSEN1 variants and cell-intrinsic hyperactivity prior to deposition of abnormal Aβ, offering prospects for the development of targeted prevention strategies for at-risk individuals.

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Section: Discussionmentioning

confidence: 99%

Carvedilol suppresses ryanodine receptor-dependent Ca²⁺bursts in human neurons bearingPSEN1variants found in early onset Alzheimer’s disease

Hori,

Ai,

Hato

et al. 2023

Preprint

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“…When Ca 2+ is released through IP3Rs, it is transferred to the mitochondria via this complex. If the levels of the ion are too high, it can lead to mPTP opening and cell death . In this work, we have observed that ENN A1 induced the pore opening so that it could act as a modulator of the IP3R–CRP75-VDAC complex.…”

Section: Discussionmentioning

confidence: 99%

Enniatins A1 and B1 Modulate Calcium Flux through Alternative Pathways beyond Mitochondria

Pérez-Fuentes,

Alvariño,

Alfonso

et al. 2024

J. Agric. Food Chem.

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Enniatins (ENNs) A1 and B1, previously considered ionophores, are emerging mycotoxins with effects on Ca 2+ homeostasis. However, their exact mechanism of action remains unclear. This study investigated how these toxins affect Ca 2+ flux in SH-SY5Y cells. ENN A1 induced Ca 2+ influx through store-operated channels (SOC). The mitochondrial uncoupler FCCP reduced this influx, suggesting that the mitochondrial status influences the toxin effect. Conversely, ENN B1 did not affect SOC but acted on another Ca 2+ channel, as shown when nickel, which directly blocks the Ca 2+ channel pore, is added. Mitochondrial function also influenced the effects of ENN B1, as treatment with FCCP reduced toxin-induced Ca 2+ depletion and uptake. In addition, both ENNs altered mitochondrial function by producing the opening of the mitochondrial permeability transition pore. This study describes for the first time that ENN A1 and B1 are not Ca 2+ ionophores and suggests a different mechanism of action for each toxin.

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“…Several mtDAMPs have also been shown to be effective activators of inflammasomes, such as the NLRP3 component, present in microglia (Marchi et al, 2023). Mitochondrion-associated membranes (MAMs) are also key sites of cell fate decisions and starting points of autophagy (de Ridder et al, 2023), while ER-stress is a well-known consequence of hypoxia (Han, Yuan, et al, 2021;Tajiri et al, 2004). Since mitochondria-MAM contact sites and associated ER-segments are all enriched at the somatic microglia-neuron junctions (Cserep et al, 2020), microglia are in an ideal position to obtain first-hand information of the ongoing cellular decision-making.…”

Section: Microglia-neuron Signalingmentioning

confidence: 99%

Microglia–neuron–vascular interactions in ischemia

Lénárt,

Cserép,

Császár

et al. 2023

Glia

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Cerebral ischemia is a devastating condition that results in impaired blood flow in the brain leading to acute brain injury. As the most common form of stroke, occlusion of cerebral arteries leads to a characteristic sequence of pathophysiological changes in the brain tissue. The mechanisms involved, and comorbidities that determine outcome after an ischemic event appear to be highly heterogeneous. On their own, the processes leading to neuronal injury in the absence of sufficient blood supply to meet the metabolic demand of the cells are complex and manifest at different temporal and spatial scales. While the contribution of non‐neuronal cells to stroke pathophysiology is increasingly recognized, recent data show that microglia, the main immune cells of the central nervous system parenchyma, play previously unrecognized roles in basic physiological processes beyond their inflammatory functions, which markedly change during ischemic conditions. In this review, we aim to discuss some of the known microglia–neuron–vascular interactions assumed to contribute to the acute and delayed pathologies after cerebral ischemia. Because the mechanisms of neuronal injury have been extensively discussed in several excellent previous reviews, here we focus on some recently explored pathways that may directly or indirectly shape neuronal injury through microglia‐related actions. These discoveries suggest that modulating gliovascular processes in different forms of stroke and other neurological disorders might have presently unexplored therapeutic potential in combination with neuroprotective and flow restoration strategies.

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The ER-mitochondria interface, where Ca2+ and cell death meet

Cited by 25 publications

References 285 publications

Carvedilol suppresses ryanodine receptor-dependent Ca²⁺bursts in human neurons bearingPSEN1variants found in early onset Alzheimer’s disease

Carvedilol suppresses ryanodine receptor-dependent Ca²⁺bursts in human neurons bearingPSEN1variants found in early onset Alzheimer’s disease

Enniatins A1 and B1 Modulate Calcium Flux through Alternative Pathways beyond Mitochondria

Microglia–neuron–vascular interactions in ischemia

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The ER-mitochondria interface, where Ca2+ and cell death meet

Cited by 25 publications

References 285 publications

Carvedilol suppresses ryanodine receptor-dependent Ca2+bursts in human neurons bearingPSEN1variants found in early onset Alzheimer’s disease

Carvedilol suppresses ryanodine receptor-dependent Ca2+bursts in human neurons bearingPSEN1variants found in early onset Alzheimer’s disease

Enniatins A1 and B1 Modulate Calcium Flux through Alternative Pathways beyond Mitochondria

Microglia–neuron–vascular interactions in ischemia

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Resources

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Carvedilol suppresses ryanodine receptor-dependent Ca²⁺bursts in human neurons bearingPSEN1variants found in early onset Alzheimer’s disease

Carvedilol suppresses ryanodine receptor-dependent Ca²⁺bursts in human neurons bearingPSEN1variants found in early onset Alzheimer’s disease