scholarly journals Cyclophilin D regulates neuronal activity-induced filopodiagenesis by fine-tuning dendritic mitochondrial calcium dynamics

2018 ◽  
Vol 146 (4) ◽  
pp. 403-415 ◽  
Author(s):  
Shaomei Sui ◽  
Jing Tian ◽  
Esha Gauba ◽  
Qi Wang ◽  
Lan Guo ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Fine Tuning ◽  
Mitochondrial Calcium ◽  
Calcium Dynamics ◽  
Cyclophilin D

Abstract MP124: De-palmitoylation of Cysteine 202 of Cyclophilin-D by Calcium is Important for the Activation of the Permeability Transition Pore

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Georgios Amanakis ◽  
Junhui Sun ◽  
Maria Fergusson ◽  
Chengyu Liu ◽  
Jeff D Molkentin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Permeability Transition ◽  
Ischemia Reperfusion ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Calcium Overload ◽  
Mitochondrial Calcium ◽  
Cyclophilin D ◽  
Perfused Heart ◽  
Knock Out

Cyclophilin-D (CypD) is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischemia/reperfusion (I/R) injury characterized by oxidative stress and calcium overload. However, the mechanism by which CypD activates PTP is poorly understood. Cysteine 202 of CypD (C202) is highly conserved across species and can undergo redox-sensitive post-translational modifications, such as S-nitrosylation and oxidation. To study the importance of C202, we developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). Hearts from these mice are protected against I/R injury. We found C202 to be abundantly S-palmitoylated under baseline conditions while C202 was de-palmitoylated during ischemia in WT hearts. To further investigate the mechanism of de-palmitoylation during ischemia, we considered the increase of matrix calcium, oxidative stress and uncoupling of ATP synthesis from the electron transport chain. We tested the effects of these conditions on the palmitoylation of CypD in isolated cardiac mitochondria. The palmitoylation of CypD was assessed using a resin-assisted capture (Acyl-RAC). We report that oxidative stress (phenylarsenide) and uncoupling (CCCP) had no effect on CypD palmitoylation (p>0.05, n=3 and n=7 respectively). However, calcium overload led to de-palmitoylation of CypD to the level observed at the end ischemia (1±0.10 vs 0.63±0.09, p=0.012, n=9). To further test the hypothesis that calcium regulates S-palmitoylation of CypD we measured S-palmitoylation of CypD in non-perfused heart lysates from global germline mitochondrial calcium uniporter knock-out mice (MCU-KO), which have reduced mitochondrial calcium and we found an increase in S-palmitoylation of CypD (WT 1±0.04 vs MCU-KO 1.603±0.11, p<0.001, n=6). The data are consistent with the hypothesis that C202 is important for the CypD mediated activation of PTP. Ischemia leads to increased matrix calcium which in turn promotes the de-palmitoylation of CypD on C202. The now free C202 can further be oxidized during reperfusion leading to the activation of PTP. Thus, S-palmitoylation and oxidation of CypD-C202 possibly target CypD to the PTP, making them potent regulators of cardiac I/R injury.

scholarly journals The mRNA Decay Factor CAR-1/LSM14 Regulates Axon Regeneration via Mitochondrial Calcium Dynamics

2020 ◽  
Vol 30 (5) ◽  
pp. 865-876.e7 ◽  
Author(s):  
Ngang Heok Tang ◽  
Kyung Won Kim ◽  
Suhong Xu ◽  
Stephen M. Blazie ◽  
Brian A. Yee ◽  
...  
Keyword(s):  
Mrna Decay ◽  
Axon Regeneration ◽  
Mitochondrial Calcium ◽  
Calcium Dynamics ◽  
Decay Factor

scholarly journals Cyclophilin D-mediated regulation of the permeability transition pore is altered in mice lacking the mitochondrial calcium uniporter

2018 ◽  
Vol 115 (2) ◽  
pp. 385-394 ◽  
Author(s):  
Randi J Parks ◽  
Sara Menazza ◽  
Kira M Holmström ◽  
Georgios Amanakis ◽  
Maria Fergusson ◽  
...  
Keyword(s):  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Calcium ◽  
Cyclophilin D ◽  
Mitochondrial Calcium Uniporter ◽  
Calcium Uniporter

Spatiotemporal calcium dynamics in single astrocytes and its modulation by neuronal activity

Cell Calcium ◽  
2014 ◽  
Vol 55 (2) ◽  
pp. 119-129 ◽  
Author(s):  
Yu-Wei Wu ◽  
Xiaofang Tang ◽  
Misa Arizono ◽  
Hiroko Bannai ◽  
Pei-Yu Shih ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Calcium Dynamics

scholarly journals Activity-dependent aberrations in gene expression and alternative splicing in a mouse model of Rett syndrome

2018 ◽  
Vol 115 (23) ◽  
pp. E5363-E5372 ◽  
Author(s):  
Sivan Osenberg ◽  
Ariel Karten ◽  
Jialin Sun ◽  
Jin Li ◽  
Shaun Charkowick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alternative Splicing ◽  
Mouse Model ◽  
Rett Syndrome ◽  
Neuronal Activity ◽  
Intron Retention ◽  
Neurodevelopmental Disorder ◽  
Fine Tuning ◽  
Global Pattern ◽  
Activity Dependent

Rett syndrome (RTT) is a severe neurodevelopmental disorder that affects about 1 in 10,000 female live births. The underlying cause of RTT is mutations in the X-linked gene, methyl-CpG-binding protein 2 (MECP2); however, the molecular mechanism by which these mutations mediate the RTT neuropathology remains enigmatic. Specifically, although MeCP2 is known to act as a transcriptional repressor, analyses of the RTT brain at steady-state conditions detected numerous differentially expressed genes, while the changes in transcript levels were mostly subtle. Here we reveal an aberrant global pattern of gene expression, characterized predominantly by higher levels of expression of activity-dependent genes, and anomalous alternative splicing events, specifically in response to neuronal activity in a mouse model for RTT. Notably, the specific splicing modalities of intron retention and exon skipping displayed a significant bias toward increased retained introns and skipped exons, respectively, in the RTT brain compared with the WT brain. Furthermore, these aberrations occur in conjunction with higher seizure susceptibility in response to neuronal activity in RTT mice. Our findings advance the concept that normal MeCP2 functioning is required for fine-tuning the robust and immediate changes in gene transcription and for proper regulation of alternative splicing induced in response to neuronal stimulation.

scholarly journals Fine-tuning activity-dependent bulk endocytosis via kinases and phosphatases

2021 ◽  
Vol 220 (12) ◽  
Author(s):  
Ira Milosevic ◽  
Michael A. Cousin
Keyword(s):  
Molecular Mechanism ◽  
Neuronal Activity ◽  
Dominant Mode ◽  
Fine Tuning ◽  
Regulation Of Activity ◽  
Synaptojanin 1 ◽  
Activity Dependent

The regulation of activity-dependent bulk endocytosis, the dominant mode of membrane retrieval in response to intense neuronal activity, is poorly understood. In this JCB issue, Peng et al. (2021. J. Cell. Biol.https://doi.org/10.1083/jcb.202011028) propose a novel molecular mechanism for the coordination of activity-dependent bulk endocytosis that builds on Minibrain kinase and its presynaptic substrate synaptojanin-1.

Regulation of Platelet Procoagulant Activity by Mitochondrial Calcium Influx

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2193-2193
Author(s):  
HyoJung Choo ◽  
Shawn M Jobe
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Conflicts Of Interest ◽  
Calcium Influx ◽  
Specific Inhibitor ◽  
Calcium Ionophore ◽  
Procoagulant Activity ◽  
Mitochondrial Calcium ◽  
Therapeutic Effects ◽  
Cyclophilin D ◽  
Passive Flow

Abstract Abstract 2193 Phosphatidylserine (PS) exposure is critical for blood coagulation. On platelets PS exposure provides a surface for the assembly of coagulation enzyme complexes. Two pathways of platelet PS exposure have been identified, an apoptotic Bax/Bak-mediated pathway and an agonist-initiated and cyclophilin D (CypD)-regulated pathway. In the agonist-initiated pathway sustained high levels of intracellular calcium that occur in strongly-stimulated platelets cause mitochondrial permeability transition pore (mPTP) formation and platelet PS exposure. Even in strongly-stimulating conditions PS exposure is limited to a subpopulation of the activated platelets. In this study we investigated how mitochondrial calcium (Ca2+mit) elevations link the intracellular processes of cytoplasmic calcium (Ca2+cyt) elevation, mPTP formation and platelet PS exposure, and identify Ca2+mit influx as a novel potential therapeutic target to manipulate platelet procoagulant activity independent of other platelet activation events. We have previously characterized the sequence of calcium and mitochondrial events that occur in procoagulant platelets and demonstrated that Ca2+cyt elevations occur prior to mPTP formation in platelets. Experiments were performed to investigate whether PS exposure could be modulated independently of elevations in Ca2+cyt through alterations in mPTP sensitivity. First we tested whether PS exposure initiated by calcium ionophore treatment was affected by the absence of CypD, a critical regulatory component of the mPTP that potentiates its calcium responsiveness. In the absence of CypD a two-threefold greater concentration of ionophore was required to initiate platelet PS exposure. Phenylarsine oxide (PAO) potentiates the calcium sensitivity of the mPTP. PAO-treated platelets required two-three fold less calcium ionophore to initiate PS exposure, and this increase was independent of Ca2+cyt elevation. Together, these experiments establish the concept that modulation of the mPTP response can affect platelet PS exposure independent of Ca2+cyt elevations. Ca2+mit influx regulates mPTP formation. Using the mitochondrial-specific and calcium-sensitive dye rhod-2, Ca2+mit was found to be rapidly elevated in strongly-stimulated platelets, and the degree of Ca2+mit elevation was closely associated with platelet PS exposure. Calcium influx in the mitochondria occurs as the result of passive flow of Ca2+cyt down its electrochemical gradient through the mitochondrial calcium uniporter (MCU), a recently identified inner-mitochondrial transmembrane channel. Treatment with the MCU-specific inhibitor Ru360 effectively prevented agonist-initiated Ca2+mit influx and platelet PS exposure. To further test the importance of Ca2+mit in the regulation of platelet PS exposure, the effects of altering prestimulatory mitochondrial transmembrane potential (ΔΨm) were examined using inhibitors of mitochondrial respiration and oxidative phosphorylation. Decreased prestimulatory ΔΨm should decrease the passive flow of calcium into the mitochondria down its electrical gradient. In these preconditioned platelets prestimulatory ΔΨm was strongly positively correlated with both agonist-initiated Ca2+mit elevation and PS exposure (R2=0.9153). Minimal correlation was observed between the degree of Ca2+cyt elevation and PS exposure (R2=0.4254). The therapeutic effects of the anti-diabetic agent metformin have been proposed to occur through inhibition of respiratory complex I, an effect that should decrease prestimulatory ΔΨm. Metformin treatment of platelets decreased prestimulatory ΔΨm, Ca2+mit elevation, and platelet PS exposure in strongly-stimulated platelets. Together, these data emphasize the importance of Ca2+mit elevation in the regulation of agonist-initiated PS exposure, and identify inhibition of Ca2+mit uptake either by MCU antagonists or by decreasing prestimulatory ΔΨm as a novel potential target in the prevention of platelet procoagulant activity. Disclosures: No relevant conflicts of interest to declare.

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