Calcium signaling around Mitochondria Associated Membranes (MAMs) - PubMed (original) (raw)

doi: 10.1186/1478-811X-9-19.

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

Affiliations

Calcium signaling around Mitochondria Associated Membranes (MAMs)

Simone Patergnani et al. Cell Commun Signal. 2011.

Abstract

Calcium (Ca2+) homeostasis is fundamental for cell metabolism, proliferation, differentiation, and cell death. Elevation in intracellular Ca2+ concentration is dependent either on Ca2+ influx from the extracellular space through the plasma membrane, or on Ca2+ release from intracellular Ca2+ stores, such as the endoplasmic/sarcoplasmic reticulum (ER/SR). Mitochondria are also major components of calcium signalling, capable of modulating both the amplitude and the spatio-temporal patterns of Ca2+ signals. Recent studies revealed zones of close contact between the ER and mitochondria called MAMs (Mitochondria Associated Membranes) crucial for a correct communication between the two organelles, including the selective transmission of physiological and pathological Ca2+ signals from the ER to mitochondria. In this review, we summarize the most up-to-date findings on the modulation of intracellular Ca2+ release and Ca2+ uptake mechanisms. We also explore the tight interplay between ER- and mitochondria-mediated Ca2+ signalling, covering the structural and molecular properties of the zones of close contact between these two networks.

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Figures

Figure 1

Figure 1

Representation of intracellular Ca2+ dynamics and MAMs proteins involved in ER-mitochondria Ca2+ cross-talk. A series of protein localized in MAMs (such as PML, AKT, grp-75, SIG-1R, Mfn-1/-2, BiP, AKT) regulate Ca2+ release from the ER and an efficient mitochondrial Ca2+ uptake, resulting in different functional outcomes. Cells generate Ca2+ signal through two mechanism that use internal and external sources of Ca2+. Calcium enters into the cell through channels and pumps situated on the plasma membrane; these are gated by voltage (VOCs) or external messengers (ROCs). A series of stimuli that act on cell surface receptors triggers the activation of PLC that catalyses the hydrolysis of phosphatidylinositol 4,5-biphosphate to IP3 and DAG. The binding of IP3 to its receptor IP3R stimulates ER Ca2+ release and consequently the transfer of Ca2+ (red dots) from ER to mitochondria. Mitochondrial surface directly interacts with the ER through contact sites defining hotspot Ca2+ signalling units. Mitochondrial Ca2+ import occurs through the mitochondrial Ca2+ uniporter (MCU) and the H+/Ca2+ exchanger LETM1; conversely, NCLX, mitochondrial Na+/Ca2+ exchanger, together with the PTP, export Ca2+ from the matrix. Ca2+ levels return to resting conditions through a series of channels and pumps: PMCA and NCX permit the ion extrusion into the extracellular milieu, SERCA (situated on the ER) and SPCA (on the Golgi apparatus) re-establish basal Ca2+ levels in intracellular stores. Abbreviations: ANT, adenosine nucleoside transporter; ETC, electron transport chain; HK, hexokinase; CD, cyclophilin D; CK, creatine kinase; BR, benzodiazepine receptor.

Figure 2

Figure 2

PML and p66Shc regulates cell span at the MAMs level. The tumor suppressor PML in resting conditions resides in a specific multi-protein complex with IP3R, PP2a and AKT, essential for a normal Ca2+ flux from ER to mitochondria and, consequently, for correct apoptosis levels (upper panel). Aging and ROS determine phosphorylation and accumulation of p66Shc in the MAMs fraction. The presence of phospho-p66Shc at the mitochondrial level determines alterations in mitochondrial homeostasis, including Ca2+ signalling, and ultimately increases apoptotic and senescence responses (lower panel).

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