Systems Approaches to Mitochondrial Calcium Signaling

Abstract

Mitochondria are essential hubs of calcium-mediated signaling networks. The organelle can take up, buffer, and release calcium ions to effectively shape intracellular calcium transients, stimulate ATP production and regulate cell death. Although, the basic mechanisms of mitochondrial calcium homeostasis have been firmly established for decades, the molecular identity of the mitochondrial calcium signaling toolkit has evaded classical bottom-up approaches. Our previous studies (1,2) have provided a compelling example of the power of systems approaches applied to mitochondrial calcium signaling to discover hitherto unknown molecular components of the calcium uniporter. Currently, we are developing computational and experimental frameworks for a systematic reconstruction of calcium-dependent signal transduction cascades in mitochondria. By combining evolutionary genomics and loss-of-function genetic and chemical screens, our systems approach holds the potential to shed light on yet unanswered questions in the field of mitochondrial calcium signaling.1. Baughman JM, Perocchi F, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK (2011). Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature. 476(7360):341-5.2. Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK (2010). MICU1 encodes a mitochondrial EF hand protein required for calcium uptake. Nature. 467(7313):291-6.