Systematic Reconstruction of Calcium Signaling Networks in Mitochondria
Final Report Abstract
With funding from the Emmy Noether Research Grant, we have developed a multidisciplinary research towards a systems-level understanding of mitochondria as dynamic receiver and integrators of signaling events, with a particular focus on the molecular reconstruction, pharmacological targeting and pathophysiological relevance of calcium-mediated, mitochondrial signal transduction cascades. We have successfully developed novel, systematic experimental and computational strategies that, together with quantitative, multiparametric measurements of mitochondrial functions in vivo and in vitro, have allowed us to identify genetic and chemical means for modulating mitochondrial calcium homeostasis and understanding the contribution of mitochondrial dysfunctions in animal models and human patients with neurodegenerative diseases. We will continue to combine biochemical, physiological and genetic approaches to characterize the function of newly discovered components of the mitochondrial calcium uniporter channel as well as of candidate proteins mediating signaling pathways between the ER and mitochondria. At the same time, we aim to extend our systematic experimental and computational approaches to reconstruct Ca2+-dependent signal transduction cascades in mitochondria, with a particular focus on Ca2+-mediated regulation of mitochondrial metabolism.
Publications
- (2014) MRM2 and MRM3 are involved in biogenesis of the large subunit of the mitochondrial ribosome. Mol. Biol. Cell. 25, 2542-55
Rorbach J, Boesch P, Gammage PA, Nicholls TJ, Pearce SF, Patel D, Hauser A, Perocchi F, Minczuk M
(See online at https://doi.org/10.1091/mbc.E14-01-0014) - (2015) Meclizine Preconditioning Protects the Kidney Against Ischemia-Reperfusion Injury. EBioMedicine 2(9):1090-101
Kishi S, Campanholle G, Gohil VM, Perocchi F, Brooks CR, Morizane R, Sabbisetti V, Ichimura T, Mootha VK, Bonventre JV
(See online at https://dx.doi.org/10.1016/j.ebiom.2015.07.035) - (2015) ProtPhylo: identification of protein-phenotype and protein-protein functional associations via phylogenetic profiling. Nucleic Acids Res. 43(W1):W160-8
Cheng Y, Perocchi F
(See online at https://doi.org/10.1093/nar/gkv455) - (2016) "K+ Efflux-Independent NLRP3 Inflammasome Activation by Small Molecules Targeting Mitochondria". Immunity. 45(4):761-773
Groß C, Mishra R, Schneider KS, Médard G, Wettmarshausen J, Dittlein DC, Shi H, Gorka O, König PA, Fromm S, Magnani G, Ćiković T, Hartjes L, Smollich J, Robertson AB, Cooper MA, Schmidt-Supprian M, Schuster M, Schroder K, Broz P, Traidl-Hoffmann C, Beutler B, Kuster B, Ruland J, Schneider S, Perocchi F, and Groß O
(See online at https://doi.org/10.1016/j.immuni.2016.08.010) - (2017) Isolation of Functional Mitochondria from Cultured Cells and Mouse Tissues. Methods Mol Biol. 1567:15-32
Wettmarshausen J, Perocchi F
(See online at https://doi.org/10.1007/978-1-4939-6824-4_2) - (2017) Optogenetic control of mitochondrial metabolism and Ca2+ signaling by mitochondria-targeted opsins. Proc Natl Acad Sci USA. 114(26):E5167-E5176
Tkatch T, Greotti E, Baranauskas G, Pendin D, Roy S, Nita LI, Wettmarshausen J, Prigge M, Yizhar O, Shirihai OS, Fishman D, Hershfinkel M, Fleidervish IA, Perocchi F, Pozzan T, Sekler I
(See online at https://doi.org/10.1073/pnas.1703623114) - (2017) Systematic Identification of MCU Modulators by Orthogonal Interspecies Chemical Screening. Mol Cell. 67(4):711-723.e7
Arduino DM, Wettmarshausen J, Vais H, Navas-Navarro P, Cheng Y, Leimpek A, Ma Z, Delrio-Lorenzo A, Giordano A, Garcia-Perez C, Médard G, Kuster B, García-Sancho J, Mokranjac D, Foskett JK, Alonso MT, Perocchi F
(See online at https://doi.org/10.1016/j.molcel.2017.07.019) - (2018) Pharmacological modulation of mitochondrial calcium homeostasis. J Physiol. 596(14):2717-2733
Arduino DM, Perocchi F
(See online at https://doi.org/10.1113/JP274959) - (2018) Prediction of Adipose Browning Capacity by Systematic Integration of Transcriptional Profiles. Cell Rep. 23(10):3112-3125
Cheng Y, Jiang L, Keipert S, Zhang S, Hauser A, Graf E, Strom T, Tschöp M, Jastroch M, Perocchi F
(See online at https://doi.org/10.1016/j.celrep.2018.05.021)
