scholarly journals Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration

Aging Cell ◽  
2021 ◽  
Author(s):  
Kerry C. Ryan ◽  
Zahra Ashkavand ◽  
Shaarika Sarasija ◽  
Jocelyn T. Laboy ◽  
Rohan Samarakoon ◽  
...  
Keyword(s):  
Calcium Uptake ◽  
Mitochondrial Activity ◽  
Mitochondrial Calcium ◽  
Mtorc1 Signaling ◽  
Mitochondrial Calcium Uptake

scholarly journals Increased Mitochondrial Calcium Uptake and Concomitant Hyperactivity by Presenilin Loss Promotes mTORC1 Signaling to Drive Neurodegeneration

2020 ◽  
Author(s):  
Kerry C. Ryan ◽  
Zahra Ashkavand ◽  
Shaarika Sarasija ◽  
Jocelyn T. Laboy ◽  
Rohan Samarakoon ◽  
...  
Keyword(s):  
Calcium Uptake ◽  
Critical Role ◽  
Mitochondrial Activity ◽  
Mitochondrial Morphology ◽  
Mitochondrial Calcium ◽  
Autophagic Flux ◽  
Age Related ◽  
Mtorc1 Signaling ◽  
Mtorc1 Pathway ◽  
Mitochondrial Calcium Uptake

Abstract BackgroundMetabolic dysfunction and protein aggregation are common characteristics that occur in age-related neurodegenerative disease, such as Alzheimer’s disease (AD). However, the mechanisms underlying these abnormalities remain poorly understood. Mutations in the presenilin genes are the primary cause of early onset familial AD, but despite their identification over 20 years ago, their role in the disease remains unclear. MethodsThe model system Caenorhabditis elegans was utilized to study the in vivo function of the highly conserved presenilin ortholog SEL-12 in the nervous system. Cell biological and biochemical assays were employed to monitor changes to proteostasis and autophagic flux in sel-12 mutants. Immunoblotting was used to assess alterations to the activity of the mTORC1 pathway, a central inhibitor of autophagy. Genetic and pharmaceutical strategies to reduce mTORC1 activity, and fluorescent reporters and biosensors were expressed in the mechanosensory neurons to measure mTORC1’s influence on proteotoxicity, neuronal health and mitochondrial morphology. Additionally, behavioral response to touch was employed to determine the role mTORC1 activity has in neuronal function in sel-12 mutants. RNA interference by standard feeding methods was used to assess the contribution of autophagy to mTORC1-mediated sel-12 defects. ResultsLoss of SEL-12 results in the hyperactivation of the mTORC1 pathway and mTORC1-dependent reduction in autophagy. This hyperactivation is caused by elevated mitochondrial calcium signaling and concomitant mitochondrial hyperactivity. Reducing mTORC1 activity improves proteostasis defects and neurodegenerative phenotypes associated with loss of SEL-12 function. Consistent with high mTORC1 activity, we find that SEL-12 loss reduces autophagy, and this reduction is prevented by limiting mitochondrial calcium uptake or mitochondrial respiration. Moreover, the improvements in proteostasis and neuronal defects in sel-12 mutants due to mTORC1 inhibition require the induction of autophagy.ConclusionSEL-12 has a critical role in mediating mitochondrial calcium homeostasis and activity. In the absence of presenilin function mitochondrial calcium uptake and mitochondrial activity is increased. This mitochondrial hyperactivity stimulates mTORC1 signaling, which inhibits autophagy and promotes proteostasis decline and neuronal dysfunction in sel-12 mutants. These data suggest that the mTORC1 pathway is a potential therapeutic target for treating AD.

scholarly journals The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart

2020 ◽  
Vol 21 (20) ◽  
pp. 7689
Author(s):  
Lo Lai ◽  
Hongyu Qiu
Keyword(s):  
Cardiac Function ◽  
Calcium Uptake ◽  
Early Stage ◽  
Contractile Activity ◽  
Critical Role ◽  
Future Research ◽  
Mitochondrial Activity ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uptake ◽  
The Impact

Calcium ion (Ca2+) plays a critical role in the cardiac mitochondria function. Ca2+ entering the mitochondria is necessary for ATP production and the contractile activity of cardiomyocytes. However, excessive Ca2+ in the mitochondria results in mitochondrial dysfunction and cell death. Mitochondria maintain Ca2+ homeostasis in normal cardiomyocytes through a comprehensive regulatory mechanism by controlling the uptake and release of Ca2+ in response to the cellular demand. Understanding the mechanism of modulating mitochondrial Ca2+ homeostasis in the cardiomyocyte could bring new insights into the pathogenesis of cardiac disease and help developing the strategy to prevent the heart from damage at an early stage. In this review, we summarized the latest findings in the studies on the cardiac mitochondrial Ca2+ homeostasis, focusing on the regulation of mitochondrial calcium uptake, which acts as a double-edged sword in the cardiac function. Specifically, we discussed the dual roles of mitochondrial Ca2+ in mitochondrial activity and the impact on cardiac function, the molecular basis and regulatory mechanisms, and the potential future research interest.

Dinuclear nitrido-bridged ruthenium complexes bearing diimine ligands

2017 ◽  
Vol 46 (41) ◽  
pp. 14256-14263 ◽  
Author(s):  
Julie Urgiles ◽  
Sarah R. Nathan ◽  
Samantha N. MacMillan ◽  
Justin J. Wilson
Keyword(s):  
Calcium Uptake ◽  
Ruthenium Complexes ◽  
Ligand Substitution ◽  
Mitochondrial Calcium ◽  
Substitution Reactions ◽  
Uptake Inhibition ◽  
Diimine Ligands ◽  
Mitochondrial Calcium Uptake ◽  
Ligand Substitution Reactions

Nitrido-bridged ruthenium complexes are synthesized via ligand substitution reactions and evaluated for mitochondrial calcium uptake inhibition.

Mitochondrial calcium uptake during ischemia is regulated by cytosolic ATP:ADP ratio

2003 ◽  
Vol 114 (2) ◽  
pp. 304 ◽  
Author(s):  
A. Wakata ◽  
A.E. Belous ◽  
C.D. Knox ◽  
J.M. Pierce ◽  
I.B. Nicoud ◽  
...  
Keyword(s):  
Calcium Uptake ◽  
Mitochondrial Calcium ◽  
Mitochondrial Calcium Uptake

OXYGEN AND MITOCHONDRIAL CALCIUM UPTAKE CAPACITY REGULATE THE INCIDENCE OF APOPTOSIS IN EPITHELIAL CELLS

Shock ◽  
2004 ◽  
Vol 21 (Supplement) ◽  
pp. 28
Author(s):  
Xueling Ma ◽  
Stefan Baeder ◽  
Weidong Du ◽  
Marion E. Schneider
Keyword(s):  
Epithelial Cells ◽  
Calcium Uptake ◽  
Mitochondrial Calcium ◽  
Uptake Capacity ◽  
Mitochondrial Calcium Uptake

Abstract 284: Loss of Micu3 Confers Cardioprotection Against Cardiac Injury

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Bao Puente ◽  
Junhui Sun ◽  
Maria Fergusson ◽  
Julia Liu ◽  
Anna Kosmach ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Calcium Uptake ◽  
Cardiac Injury ◽  
Mitochondrial Calcium ◽  
Wild Type ◽  
Ischemic Reperfusion ◽  
Mitochondrial Calcium Uptake

Background: Mitochondrial calcium flux and signaling is integral to cardiac function and contraction. However, during pathologic conditions such as ischemic/reperfusion injury, mitochondrial calcium overload can induce the opening of the mitochondrial permeability transitioning pore (PTP), resulting in the collapse of mitochondrial membrane potential, ATP depletion, and generation of reactive oxygen species, all together leading to cell death. Hence, modulation of mitochondrial calcium and inhibition of the PTP is a promising target for cardioprotection and prevention of cardiomyocyte death. The mitochondrial calcium uniporter (MCU) complex mediates rapid mitochondrial calcium uptake. MICU3 is a regulator of the MCU complex and has been shown to be a highly potent stimulator of MCU-dependent calcium uptake in neuronal cells. We found that MICU3 is expressed in hearts and we therefore investigated the role of MICU3 in the heart. We examined the role of MICU3 in the development of hypertrophy and in a separate study we examined the response to ischemic-reperfusion (I/R) injury. Given its role in regulating mitochondrial calcium uptake, we hypothesized that loss of MICU3 confers protection against cardiac injury. Methods: Mice with global deletion of Micu3 (Micu3 -/- ) were created utilizing CRISPR-Cas9 technology. Adult knockout and littermate wild type mice were treated with Isoproterenol (15mg/kg/day) for two weeks to induce hypertrophy. Echocardiograms were performed at baseline and after treatment to assess changes in left ventricular size and function. I/R injury was studied using Langendorff ex vivo perfused heart system, exposing knockout and wild type hearts to 20 minutes of ischemia and 90 minutes of reperfusion. Hemodynamic data and infarct size were collected and compared. Student t-test and 2-way ANOVA were used for statistical analysis. Result: Micu3 -/- mice had normal cardiac function at baseline. There was no sex difference in cardiac function. Micu3 -/- mice continued to show normal function after 2 weeks of treatment with Isoproterenol, whereas wild type mice exhibited depressed function (median FS 35% vs. 24% p = 0.0001, EF 64% vs. 50% p = 0.0001). Wild type mice developed LV dilation from baseline (median 4.15mm vs. 4.57mm, p = 0.0014), whereas LV dimension remained stable in Micu3 -/- mice (median 4.12mm vs. 4.18mm, p= 0.9892). Micu3 - /- mice were also protected from I/R injury. Compared to wild types, Micu3 -/- hearts demonstrated less contractile dysfunction at end reperfusion (median rate pressure product 62% vs. 41%, p = 0.002), and significantly smaller infarct size (median 33% vs. 53%, p = 0.0001). Conclusion: Loss of MICU3 confers cardioprotection against ischemic reperfusion injury and Isoproterenol induced cardiac dysfunction.

Protection of mitochondrial function by mannitol in ischemic acute renal failure

1984 ◽  
Vol 247 (2) ◽  
pp. F365-F369 ◽  
Author(s):  
R. W. Schrier ◽  
P. E. Arnold ◽  
J. A. Gordon ◽  
T. J. Burke
Keyword(s):  
Calcium Uptake ◽  
Cellular Level ◽  
Cell Swelling ◽  
Mitochondrial Calcium ◽  
Release Rates ◽  
Ischemic Insult ◽  
Cellular Protection ◽  
Functional Changes ◽  
Mitochondrial Calcium Uptake ◽  
Ischemic Acute Renal Failure

The effect of isotonic mannitol to provide protection against ischemic renal injury was examined in the dog. Mannitol treatment attenuated the fall in glomerular filtration rate at both 1 and 24 h after the ischemic insult. The functional changes were associated with profound cellular protection, since normal mitochondrial respiration, mitochondrial calcium uptake and release rates were preserved, and excessive mitochondrial calcium accumulation was prevented. These effects at the cellular level appear critical to the protective effect of mannitol after ischemia and are most likely due to prevention of cell swelling.

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