Cytoplasmic calcium spikes and oscillations elicited by a wide range of hormones and growth factors are propagated to the mitochondria to control several fundamental aspects of cell function including cell metabolism and survival. Delivery of the calcium signal to the mitochondria during short lasting Ca2+ release events is dependent on a local [Ca2+] regulation between IPs-activated endoplasmic reticulum (ER) Ca2+ release sites and mitochondrial Ca2+ uptake sites. This project aims at delineating the mechanisms that enable the local Ca2+ talk between ER and mitochondria. Our principal hypothesis is that the spatial relationship and calcium coupling between ER and mitochondria is controlled at several levels that include organellar motility, the ER-mitochondrial protein linkage and the function of the interacting channels. We propose that the motility of the organelles is controlled by Ca2+ to bring together ER and mitochondria at the sites of the ER Ca2+ mobilization. We postulate that the Ca2+-dependent regulation of motility is mediated by calmodulin and myosin V. We propose that at the sites of close associations of smooth or rough ER and mitochondria, protein links are formed to stabilize the interactions and to initiate a specialization in mitochondrial function. Furthermore, we suggest that at the ER-mitochondrial interface, both the IP3 receptor and the VDAC function is regulated, in part by Ca2+, to increase the efficacy of the Ca2* transfer to the mitochondria. As a major evidence for the local communication, our studies have shown that elementary calcium signals, calcium sparks propagate to the mitochondria giving rise to miniature, single mitochondrial calcium increases, referred as """"""""calcium marks"""""""". Our data also indicated that mitochondrial calcium uptake contributes to the shaping of the elementary calcium signals in the cytoplasm. Furthermore, we have shown that the mitochondrial signal is more sensitive to suppression of Ca2+ release (IP3 receptor down-regulation, IP3 buffering and suboptimal ER Ca2* loading) than the cytoplasmic calcium signal. The studies have also revealed restriction of the Ca2+ transfer through the outer mitochondrial membrane and Ca2+-dependent facilitation of the Ca2+ uptake through the inner membrane. Furthermore, we have set up novel approaches for simultaneous evaluation of [Ca2+] and mitochondrial motility and described a Ca2+-dependent homeostatic control of mitochondrial movements. We will also introduce synthetic ER-mitochondrial crosslinkers and some novel multi-parameter fluorescence imaging methods to define the critical elements for the organization of the ER-mitochondrial Ca2+ coupling. Understanding the mechanisms of mitochondrial calcium signaling will provide a key component in elucidating the control of the fundamental mitochondrial contribution to cell survival and cell death in a wide range of physiological and pathological processes.
| Joseph, Suresh K; Young, Michael P; Alzayady, Kamil et al. (2018) Redox regulation of type-I inositol trisphosphate receptors in intact mammalian cells. J Biol Chem 293:17464-17476 |
| Csordás, György; Weaver, David; Hajnóczky, György (2018) Endoplasmic Reticulum-Mitochondrial Contactology: Structure and Signaling Functions. Trends Cell Biol 28:523-540 |
| Vincent, Amy E; Turnbull, Doug M; Eisner, Veronica et al. (2017) Mitochondrial Nanotunnels. Trends Cell Biol 27:787-799 |
| Debattisti, Valentina; Gerencser, Akos A; Saotome, Masao et al. (2017) ROS Control Mitochondrial Motility through p38 and the Motor Adaptor Miro/Trak. Cell Rep 21:1667-1680 |
| Lavorato, Manuela; Iyer, V Ramesh; Dewight, Williams et al. (2017) Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges. Proc Natl Acad Sci U S A 114:E849-E858 |
| Eisner, Verónica; Cupo, Ryan R; Gao, Erhe et al. (2017) Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity. Proc Natl Acad Sci U S A 114:E859-E868 |
| Bagur, Rafaela; Hajnóczky, György (2017) Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling. Mol Cell 66:780-788 |
| Seifert, Erin L; Ligeti, Erzsébet; Mayr, Johannes A et al. (2015) The mitochondrial phosphate carrier: Role in oxidative metabolism, calcium handling and mitochondrial disease. Biochem Biophys Res Commun 464:369-75 |
| Picard, Martin; McManus, Meagan J; Csordás, György et al. (2015) Trans-mitochondrial coordination of cristae at regulated membrane junctions. Nat Commun 6:6259 |
| Hajnóczky, György; Booth, David; Csordás, György et al. (2014) Reliance of ER-mitochondrial calcium signaling on mitochondrial EF-hand Ca2+ binding proteins: Miros, MICUs, LETM1 and solute carriers. Curr Opin Cell Biol 29:133-41 |
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