ORP5 Transfers Phosphatidylserine to Mitochondria and Regulates Mitochondrial Calcium Uptake at Endoplasmic Reticulum - Mitochondria Contact Sites

2019 ◽  
Author(s):  
Leila Rochin ◽  
Cécile Sauvanet ◽  
Eeva Jääskeläinen ◽  
Audrey Houcine ◽  
Annukka Kivela ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Uptake ◽  
Mitochondrial Calcium ◽  
Contact Sites ◽  
Mitochondrial Calcium Uptake

scholarly journals ORP5 Transfers Phosphatidylserine To Mitochondria And Regulates Mitochondrial Calcium Uptake At Endoplasmic Reticulum - Mitochondria Contact Sites

2019 ◽  
Author(s):  
Leila Rochin ◽  
Cécile Sauvanet ◽  
Eeva Jääskeläinen ◽  
Audrey Houcine ◽  
Amita Arora ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
Calcium Uptake ◽  
Vesicular Transport ◽  
Mitochondrial Calcium ◽  
Mitochondrial Membranes ◽  
Membrane Contact Sites ◽  
Contact Sites ◽  
Membrane Contact ◽  
Mitochondrial Calcium Uptake

SUMMARYMitochondria are dynamic organelles essential for cell survival whose structural and functional integrity rely on selective and regulated transport of lipids from/to the endoplasmic reticulum (ER) and across the two mitochondrial membranes. As they are not connected by vesicular transport, the exchange of lipids between ER and mitochondria occurs at sites of close organelle apposition called membrane contact sites. However, the mechanisms and proteins involved in these processes are only beginning to emerge. Here, we show that ORP5/8 mediate non-vesicular transport of Phosphatidylserine (PS) from the ER to mitochondria in mammalian cells. We also show that ER-mitochondria contacts where ORP5/8 reside are physically and functionally linked to the MIB/MICOS complexes that bridge the mitochondrial membranes, cooperating with them to facilitate PS transfer from the ER to the mitochondria. Finally, we show that ORP5 but not ORP8, additionally regulates import of calcium to mitochondria and consequently cell senescence.

scholarly journals Mitochondria-lysosome contacts regulate mitochondrial Ca2+dynamics via lysosomal TRPML1

2020 ◽  
Vol 117 (32) ◽  
pp. 19266-19275 ◽  
Author(s):  
Wesley Peng ◽  
Yvette C. Wong ◽  
Dimitri Krainc
Keyword(s):  
Calcium Uptake ◽  
Calcium Release ◽  
Transient Receptor Potential ◽  
Mitochondrial Dynamics ◽  
Contact Dynamics ◽  
Mitochondrial Calcium ◽  
Calcium Dynamics ◽  
Voltage Dependent Anion Channel ◽  
Contact Sites ◽  
Mitochondrial Calcium Uptake

Mitochondria and lysosomes are critical for cellular homeostasis, and dysfunction of both organelles has been implicated in numerous diseases. Recently, interorganelle contacts between mitochondria and lysosomes were identified and found to regulate mitochondrial dynamics. However, whether mitochondria–lysosome contacts serve additional functions by facilitating the direct transfer of metabolites or ions between the two organelles has not been elucidated. Here, using high spatial and temporal resolution live-cell microscopy, we identified a role for mitochondria–lysosome contacts in regulating mitochondrial calcium dynamics through the lysosomal calcium efflux channel, transient receptor potential mucolipin 1 (TRPML1). Lysosomal calcium release by TRPML1 promotes calcium transfer to mitochondria, which was mediated by tethering of mitochondria–lysosome contact sites. Moreover, mitochondrial calcium uptake at mitochondria–lysosome contact sites was modulated by the outer and inner mitochondrial membrane channels, voltage-dependent anion channel 1 and the mitochondrial calcium uniporter, respectively. Since loss of TRPML1 function results in the lysosomal storage disorder mucolipidosis type IV (MLIV), we examined MLIV patient fibroblasts and found both altered mitochondria–lysosome contact dynamics and defective contact-dependent mitochondrial calcium uptake. Thus, our work highlights mitochondria–lysosome contacts as key contributors to interorganelle calcium dynamics and their potential role in the pathophysiology of disorders characterized by dysfunctional mitochondria or lysosomes.

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.

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