Mitochondria-Associated Membranes (MAMs) as Hotspot Ca2+ Signaling Units

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

doi:10.1007/978-94-007-2888-2_17

Cited by 73 publications

(43 citation statements)

References 172 publications

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“…16 Growing evidence indicates that specific proteins residing at the ER and MAMs are able to regulate mitochondrial Ca 2 þ uptake. 17,34 We pursued the hypothesis that PTEN could act as a tumor suppressor, at least in part, by modulating the transmission of Ca 2 þ from the ER to mitochondria.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, numerous other proteins have been characterized at MAMs, underlying the importance of this subcellular domain for signaling cell fate choices. 17 Here, we provide unprecedented evidence that a fraction of cellular PTEN is localized at the ER and MAMs. We observed that during Ca 2 þ -dependent apoptosis the localization of PTEN to the ER further increase.…”

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confidence: 86%

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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%

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confidence: 86%

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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“…Transient expression of VDAC enhanced the amplitude of agonist-dependent increases in mitochondrial matrix Ca 2+ concentration by allowing the fast diffusion of Ca 2+ from ER release sites to the inner mitochondrial membrane [118]. The specific sites of physical association between the ER and mitochondria, known as mitochondria associated membranes (MAMs), include VDAC among the proteins present at these junctions [259]. The mitochondrial chaperone glucose-regulated protein 75 (grp75) has been proposed to mediate the molecular interaction of VDAC1 with the ER Ca 2+ release channel, IP 3 R, and that a chaperone-mediated conformational coupling of the proteins enables better transfer of the Ca 2+ ions from the ER to the mitochondria [260].…”

Section: Er-mitochondria Ca 2+ Transport Vdac and Apoptosismentioning

confidence: 99%

The mitochondrial voltage-dependent anion channel 1 in tumor cells

Shoshan‐Barmatz

Ben-Hail

Admoni

et al. 2015

Biochimica et Biophysica Acta (BBA) - Biomembranes

209

254

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VDAC1 is found at the crossroads of metabolic and survival pathways. VDAC1 controls metabolic cross-talk between mitochondria and the rest of the cell by allowing the influx and efflux of metabolites, ions, nucleotides, Ca2+ and more. The location of VDAC1 at the outer mitochondrial membrane also enables its interaction with proteins that mediate and regulate the integration of mitochondrial functions with cellular activities. As a transporter of metabolites, VDAC1 contributes to the metabolic phenotype of cancer cells. Indeed, this protein is over-expressed in many cancer types, and silencing of VDAC1 expression induces an inhibition of tumor development. At the same time, along with regulating cellular energy production and metabolism, VDAC1 is involved in the process of mitochondria-mediated apoptosis by mediating the release of apoptotic proteins and interacting with anti-apoptotic proteins. The engagement of VDAC1 in the release of apoptotic proteins located in the inter-membranal space involves VDAC1 oligomerization that mediates the release of cytochrome c and AIF to the cytosol, subsequently leading to apoptotic cell death. Apoptosis can also be regulated by VDAC1, serving as an anchor point for mitochondria-interacting proteins, such as hexokinase (HK), Bcl2 and Bcl-xL, some of which are also highly expressed in many cancers. By binding to VDAC1, HK provides both a metabolic benefit and apoptosis-suppressive capacity that offer the cell a proliferative advantage and increase its resistance to chemotherapy. Thus, these and other functions point to VDAC1 as an excellent target for impairing the re-programed metabolism of cancer cells and their ability to evade apoptosis. Here, we review current evidence pointing to the function of VDAC1 in cell life and death, and highlight these functions in relation to both cancer development and therapy. In addressing the recently solved 3D structures of VDAC1, this review will point to structure-function relationships of VDAC as critical for deciphering how this channel can perform such a variety of roles, all of which are important for cell life and death. Finally, this review will also provide insight into VDAC function in Ca2+ homeostasis, protection against oxidative stress, regulation of apoptosis and involvement in several diseases, as well as its role in the action of different drugs. We will discuss the use of VDAC1-based strategies to attack the altered metabolism and apoptosis of cancer cells. These strategies include specific siRNA able to impair energy and metabolic homeostasis, leading to arrested cancer cell growth and tumor development, as well VDAC1-based peptides that interact with anti-apoptotic proteins to induce apoptosis, thereby overcoming the resistance of cancer cell to chemotherapy. Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target. This article is part of a Special ...

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“…, 2015). Similarly, ER–mitochondrial interaction may be important for the Pink1-Parkin pathway, which is implicated in PD (Erpapazoglou and Corti, 2015), and Ca 2+ homeostasis (Bononi et al. , 2012).…”

Section: Introductionmentioning

confidence: 99%