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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051526-14
Application #
7749940
Study Section
Cell Structure and Function (CSF)
Program Officer
Abraham, Kristin M
Project Start
1996-08-20
Project End
2012-04-18
Budget Start
2010-01-01
Budget End
2012-04-18
Support Year
14
Fiscal Year
2010
Total Cost
$300,762
Indirect Cost
Name
Thomas Jefferson University
Department
Pathology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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
Nguyen, Tammy T; Oh, Sang S; Weaver, David et al. (2014) Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc Natl Acad Sci U S A 111:E3631-40
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
Eisner, Verónica; Lenaers, Guy; Hajnóczky, György (2014) Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling. J Cell Biol 205:179-95
Eisner, Verónica; Csordás, György; Hajnóczky, György (2013) Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle - pivotal roles in Ca²⁺ and reactive oxygen species signaling. J Cell Sci 126:2965-78
Csordás, György; Golenár, Tünde; Seifert, Erin L et al. (2013) MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca²⁺ uniporter. Cell Metab 17:976-87
Mallilankaraman, Karthik; Cárdenas, César; Doonan, Patrick J et al. (2012) MCUR1 is an essential component of mitochondrial Ca2+ uptake that regulates cellular metabolism. Nat Cell Biol 14:1336-43
Csordas, Gyorgy; Varnai, Peter; Golenar, Tunde et al. (2012) Calcium transport across the inner mitochondrial membrane: molecular mechanisms and pharmacology. Mol Cell Endocrinol 353:109-13
Yi, Muqing; Weaver, David; Eisner, Verónica et al. (2012) Switch from ER-mitochondrial to SR-mitochondrial calcium coupling during muscle differentiation. Cell Calcium 52:355-65

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