Ca2+ transfer from the ER to mitochondria: When, how and why

Meneghesso, Gaudenzio; Marchi, Saverio; Bonora, Massimo; Aguiari, Paola; Bononi, Angela; Stefani, Diego De; Giorgi, Carlotta; Leo, Sara; Rimessi, Alessandro; Siviero, Roberta; Zecchini, Erika; Pinton, Paolo

doi:10.1016/j.bbabio.2009.03.015

Cited by 419 publications

(344 citation statements)

References 137 publications

(141 reference statements)

Supporting

Mentioning

317

Contrasting

Unclassified

Order By: Relevance

“…through L-type Ca 2+ channel and NCX (sodium-calcium exchanger)). 16 Although ryanodine receptors (RyRs) are the major cardiac SR/ER Ca 2+ -release channels involved in excitation-contraction coupling (ECC) 17 and ischemia-reperfusion (IR) injury, 18 recent studies reported an increasing role for inositol 1,4,5-trisphosphate receptors (IP 3 Rs) Ca 2+ -release channels in the modulation of ECC and cell death. 19,20 Ca 2+ -handling proteins of ER and mitochondria are highly concentrated at mitochondria-associated ER membranes (MAMs), providing a direct and proper mitochondrial Ca 2+ signaling, including VDAC, Grp75 and IP 3 R1.…”

mentioning

confidence: 99%

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

Gomez¹,

Thiebaut²,

Paillard³

et al. 2015

Cell Death Differ

108

View full text Add to dashboard Cite

Glycogen synthase kinase-3β (GSK3β) is a multifunctional kinase whose inhibition is known to limit myocardial ischemiareperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/ endoplasmic reticulum (SR/ER) are key players in cell death signaling. Their involvement in myocardial ischemia-reperfusion injury has gained recognition recently, but the underlying mechanisms are not yet well understood. We questioned here whether GSK3β might have a role in the Ca 2+ transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3β protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3β specifically interacted with the inositol 1,4,5-trisphosphate receptors (IP 3 Rs) Ca 2+ channeling complex in MAMs. We demonstrated that both pharmacological and genetic inhibition of GSK3β decreased protein interaction of IP 3 R with the Ca 2+ channeling complex, impaired SR/ER Ca 2+ release and reduced the histamine-stimulated Ca 2+ exchange between SR/ER and mitochondria in cardiomyocytes. During hypoxia reoxygenation, cell death is associated with an increase of GSK3β activity and IP 3 R phosphorylation, which leads to enhanced transfer of Ca 2+ from SR/ER to mitochondria. Inhibition of GSK3β at reperfusion reduced both IP 3 R phosphorylation and SR/ER Ca 2+ release, which consequently diminished both cytosolic and mitochondrial Ca 2+ concentrations, as well as sensitivity to apoptosis. We conclude that inhibition of GSK3β at reperfusion diminishes Ca 2+ leak from IP 3 R at MAMs in the heart, which limits both cytosolic and mitochondrial Ca 2+ overload and subsequent cell death. Glycogen synthase kinase-3 (GSK3) was originally identified as a phosphorylating kinase for glycogen synthase. 1,2 It has two isoforms, α and β, that possess strong homology in their kinase domains with, however, distinct functions. 3 GSK3 is constitutively active but it can be inhibited by phosphorylation on serine 21 (Ser21) for GSK3α and Ser9 for GSK3β. 4 In the heart, GSK3β has several important roles in cardiac hypertrophy 5 and ischemia-reperfusion (IR) injury. 6 Accumulating evidence indicates that phospho-Ser9-GSK3β-mediated cytoprotection is achieved by an increased threshold for permeability transition pore (PTP) opening. [6][7][8][9] The mechanism by which GSK3β delays PTP opening still remains unclear. It has been reported that GSK3β could interact with ANT at the inner mitochondrial membrane in the heart 9 and/or to phosphorylate voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) in cancer cells. 10,11 GSK3β also has other proposed mechanisms of action, including a poorly characterized role in calcium (Ca 2+ ) homeostasis regulation 12 and protein-protein interactions, 9 as well as functions in different subcellular fractions such as the nucleus, cytosol and mitochondria. 13 Reperfusion is the most powerful intervention to salvage ischemic myocardium. However, it can also paradoxically lead to ca...

show abstract

mentioning

confidence: 99%

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

Gomez¹,

Thiebaut²,

Paillard³

et al. 2015

Cell Death Differ

108

View full text Add to dashboard Cite

show abstract

“…19,20 Mitochondrial [Ca 2 þ ] is commonly regarded as an important determinant in cell sensitivity to apoptotic stimuli. 21 Indeed, mitochondrial Ca 2 þ accumulation acts as a 'priming signal' sensitizing the organelle and promoting the release of caspase cofactors, both in isolated mitochondria as well as in intact cells. 22,23 In this context, ER-mitochondria contacts mediate the tight and efficient Ca 2 þ transmission between the two organelles and thus could represent a potential regulatory site for cell death signals.…”

mentioning

confidence: 99%

VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria

et al. 2011

View full text Add to dashboard Cite

Voltage-dependent anion channels (VDACs) are expressed in three isoforms, with common channeling properties and different roles in cell survival. We show that VDAC1 silencing potentiates apoptotic challenges, whereas VDAC2 has the opposite effect. Although all three VDAC isoforms are equivalent in allowing mitochondrial Ca 2 þ loading upon agonist stimulation, VDAC1 silencing selectively impairs the transfer of the low-amplitude apoptotic Ca 2 þ signals. Co-immunoprecipitation experiments show that VDAC1, but not VDAC2 and VDAC3, forms complexes with IP 3 receptors, an interaction that is further strengthened by apoptotic stimuli. These data highlight a non-redundant molecular route for transferring Ca 2 þ signals to mitochondria in apoptosis.

show abstract

“…Mitochondrial architecture is important for crucial mitochondrial functions, including ATP generation via oxidative phosphorylation (OXPHOS), calcium homeostasis and programmed cell death (apoptosis) (Frey and Mannella , 2000 ;Frezza et al , 2006 ;Clapham , 2007 ;Strauss et al , 2008 ;Rizzuto et al , 2009 ;Martins de Brito and Scorrano , 2010 ;Davies et al , 2011 ;Green et al , 2011 ). Accordingly, alterations of mitochondrial morphology are a hallmark of numerous human diseases, ranging from myopathies, neuropathies and neurodegenerative disorders to metabolic diseases and different types of cancer.…”

Section: Implications Of Minos Functions For Human Diseasementioning

confidence: 99%

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

Zerbes¹,

Klei

Veenhuis

et al. 2012

Biological Chemistry

120

View full text Add to dashboard Cite

: Mitofilin proteins are crucial organizers of mitochondrial architecture. They are located in the inner mitochondrial membrane and interact with several protein complexes of the outer membrane, thereby generating contact sites between the two membrane systems of mitochondria. Within the inner membrane, mitofilins are part of hetero-oligomeric protein complexes that have been termed the mitochondrial inner membrane organizing system (MINOS). MINOS integrity is required for the maintenance of the characteristic morphology of the inner mitochondrial membrane, with an inner boundary region closely apposed to the outer membrane and cristae membranes, which form large tubular invaginations that protrude into the mitochondrial matrix and harbor the enzyme complexes of the oxidative phosphorylation machinery. MINOS deficiency comes along with a loss of crista junction structures and the detachment of cristae from the inner boundary membrane. MINOS has been conserved in evolution from unicellular eukaryotes to humans, where alterations of MINOS subunits are associated with multiple pathological conditions.

show abstract

Ca2+ transfer from the ER to mitochondria: When, how and why

Cited by 419 publications

References 137 publications

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

VDAC1 selectively transfers apoptotic Ca2+ signals to mitochondria

Mitofilin complexes: conserved organizers of mitochondrial membrane architecture

Contact Info

Product

Resources

About