Mitochondrial Ca2+ and apoptosis

Giorgi, Carlotta; Baldassari, Federica; Bononi, Angela; Bonora, Massimo; Marchi, Elena De; Marchi, Saverio; Missiroli, Sonia; Patergnani, Simone; Rimessi, Alessandro; Suski, Jan M.; Wieckowski, Mariusz R.; Pinton, Paolo

doi:10.1016/j.ceca.2012.02.008

Cited by 406 publications

(265 citation statements)

References 123 publications

(110 reference statements)

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“…15 Mitochondrial Ca 2 þ accumulation favors cell death and this notion is supported by numerous previous examples of pro-and antiapoptotic proteins capable of enhancing or reducing Ca 2 þ signals, respectively. 33 For this reason, the remodeling of the Ca 2 þ signaling machinery in the ER and mitochondria of cancer cells seems imminent during oncogenic transformation, to limit death-inducing Ca 2 þ signals during cancer. 16 Growing evidence indicates that specific proteins residing at the ER and MAMs are able to regulate mitochondrial Ca 2 þ uptake.…”

Section: Discussionmentioning

confidence: 99%

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

et al. 2013

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The tumor suppressor activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10) is thought to be largely attributable to its lipid phosphatase activity. PTEN dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate to directly antagonize the phosphoinositide 3-kinase-Akt pathway and prevent the activating phosphorylation of Akt. PTEN has also other proposed mechanisms of action, including a poorly characterized protein phosphatase activity, protein-protein interactions, as well as emerging functions in different compartment of the cells such as nucleus and mitochondria. We show here that a fraction of PTEN protein localizes to the endoplasmic reticulum (ER) and mitochondriaassociated membranes (MAMs), signaling domains involved in calcium ( 2 þ ) transfer from the ER to mitochondria and apoptosis induction. We demonstrate that PTEN silencing impairs ER Ca 2 þ release, lowers cytosolic and mitochondrial Ca 2 þ transients and decreases cellular sensitivity to Ca 2 þ -mediated apoptotic stimulation. Specific targeting of PTEN to the ER is sufficient to enhance ER-to-mitochondria Ca 2 þ transfer and sensitivity to apoptosis. PTEN localization at the ER is further increased during Ca 2 þ -dependent apoptosis induction. Importantly, PTEN interacts with the inositol 1,4,5-trisphosphate receptors (IP3Rs) and this correlates with the reduction in their phosphorylation and increased Ca 2 þ release. We propose that ER-localized PTEN regulates Ca 2 þ release from the ER in a protein phosphatase-dependent manner that counteracts Akt-mediated reduction in Ca 2 þ release via IP3Rs. These findings provide new insights into the mechanisms and the extent of PTEN tumor-suppressive functions, highlighting new potential strategies for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

et al. 2013

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“…Mitochondrial damage has been linked to NLRP3 activation, and excessive mitochondrial Ca 2 þ uptake, in turn, leads to mitochondrial dysfunction 30 . This evidence suggests that an abnormal basal [Ca 2 þ ] or inter-organelle Ca 2 þ flux affects the mitochondrial responsivity of Ca 2 þ -dependent pro-inflammatory signals triggered by P. aeruginosa.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis

et al. 2015

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The common pathological manifestation of cystic fibrosis (CF) is associated with an excessive lung inflammatory response characterized by interleukin-1b accumulation. CF airway epithelial cells show an exacerbated pro-inflammatory response to Pseudomonas aeruginosa; however, it is unclear whether this heightened inflammatory response is intrinsic to cells lacking CF transmembrane conductance regulator (CFTR). Here we demonstrate that the degree and quality of the inflammatory response in CF are supported by P. aeruginosadependent mitochondrial perturbation, in which flagellin is the inducer and mitochondrial Ca 2 þ uniporter (MCU) is a signal-integrating organelle member for NLRP3 activation and IL-1b and IL-18 processing. Our work elucidates the regulation of the NLRP3 inflammasome by mitochondrial Ca 2 þ in the P. aeruginosa-dependent inflammatory response and deepens our understanding of the significance of mitochondria in the Ca 2 þ -dependent control of inflammation. hronic airway infection by Pseudomonas aeruginosa is a common pathological manifestation in cystic fibrosis (CF) patients, and the role of calcium ions (Ca 2 þ ) in this process seems pivotal in controlling the P. aeruginosa-dependent innate immune response 1 . This manifestation is associated with an excessive inflammatory response characterized by the accumulation of large amounts of cytokines, including interleukin-1b (IL-1b) 2 .Previous studies support the role of IL-1b in the pathogenesis of CF inflammatory lung disease. The levels of IL-1b are increased in bronchoalveolar lavage fluid of CF patients 2,3 , and polymorphisms in the IL-1b gene have been associated with varying degrees of disease severity 4 .The maturation of IL-1b and IL-18 are directed by the caspase-1 (casp-1)-activating multiprotein platform, the inflammasome. Four distinct inflammasomes that contain a nucleotidebinding and oligomerization domain (NOD)-like receptor have been identified: NLRP1, IPAF, NLRP3 and AIM2 (ref. 5). NODlike receptors (NLRs) are intracellular pattern-recognition receptors that recognize pathogen-associated molecular patterns and activate the pro-inflammatory response through specific pathways 6 . It is generally accepted that the release of IL-1b and IL-18 require two distinct signals; however, the nature of these signals during inflammation is not completely defined. Studies indicate that the 'first signal' can be triggered by various pathogen-associated molecular patterns following Toll-like receptor (TLR) activation, which induces the synthesis of proIL-1b and proIL-18. The 'second signal' is provided by activation of the inflammasome and casp-1, leading to IL-1b and IL-18 processing.P. aeruginosa reportedly activates IPAF, leading to IL-1b processing 7 . IPAF interacts directly with procaspase-1, which contains the N-terminal caspase recruitment domain 8 . However, maximum casp-1 activation in response to IPAF agonists requires the involvement of apoptosis-associated specklike protein (ASC) 9,10 , a bipartite, caspase recruitment domainand py...

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“…It is well known that mitochondrial alterations cause defects in Ca 2+ uptake by the organelle (15). The dynamics of agonist-dependent Ca 2+ concentration changes were measured taking advantages of a mitochondria-targeted chimera of the Ca 2+ -sensitive photoprotein aequorin (16).…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

Chiabrando

Marro²,

Mercurio³

et al. 2012

J. Clin. Invest.

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170

235

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Feline leukemia virus subgroup C receptor 1 (FLVCR1) is a cell membrane heme exporter that maintains the balance between heme levels and globin synthesis in erythroid precursors. It was previously shown that Flvcr1-null mice died in utero due to a failure of erythropoiesis. Here, we identify Flvcr1b, a mitochondrial Flvcr1 isoform that promotes heme efflux into the cytoplasm. Flvcr1b overexpression promoted heme synthesis and in vitro erythroid differentiation, whereas silencing of Flvcr1b caused mitochondrial heme accumulation and termination of erythroid differentiation. Furthermore, mice lacking the plasma membrane isoform (Flvcr1a) but expressing Flvcr1b had normal erythropoiesis, but exhibited hemorrhages, edema, and skeletal abnormalities. Thus, FLVCR1b regulates erythropoiesis by controlling mitochondrial heme efflux, whereas FLVCR1a expression is required to prevent hemorrhages and edema. The aberrant expression of Flvcr1 isoforms may play a role in the pathogenesis of disorders characterized by an imbalance between heme and globin synthesis.

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Mitochondrial Ca2+ and apoptosis

Cited by 406 publications

References 123 publications

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

Identification of PTEN at the ER and MAMs and its regulation of Ca2+ signaling and apoptosis in a protein phosphatase-dependent manner

Mitochondrial Ca2+-dependent NLRP3 activation exacerbates the Pseudomonas aeruginosa-driven inflammatory response in cystic fibrosis

The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation

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