Biologia

Nature Reviews Molecular Cell Biology | AOP, published online 1 August 2012; doi:10.1038/nrm3412

REVIEWS
Mitochondria as sensors and regulators of calcium signalling
Rosario Rizzuto, Diego De Stefani, Anna Raffaello and Cristina Mammucari

Abstract | During the past two decades calcium (Ca2+) accumulation in energized mitochondria has emerged as a biological process of utmostphysiological relevance. Mitochondrial Ca2+ uptake was shown to control intracellular Ca2+ signalling, cell metabolism, cell survival and other cell-type specific functions by buffering cytosolic Ca2+ levels and regulating mitochondrial effectors. Recently, the identity of mitochondrial Ca2+ transporters has been revealed, opening new perspectives for investigation and molecular intervention.
Immunologicalsynapse
The site of functional apposition between an antigen-presenting cell (APC) and a T cell. During antigen presentation, the T cell undergoes a gross morphological rearrangement, with T cell receptors, adhesion molecules, cytoskeletal elements and organelles (including mitochondria) spatially relocating at clusters at the contact site with the APC.

Energized mitochondria
When oxidizablesubstrates are provided to mitochondria, electrons are fed into the respiratory chain, which couples electron flow to proton pumps across the inner mitochondrial membrane. An electrochemical proton gradient is established that drives ATP synthesis and provides the thermodynamic force for Ca2+ accumulation in these energized mitochondria. Department of Biomedical Sciences, University of Padua andCNR Neuroscience Institute, Via G. Colombo 3, 35131 Padua, Italy. Correspondence to R.R.  e‑mail: rosario.rizzuto@unipd.it doi:10.1038/nrm3412 Published online 1 August 2012

During the past century, calcium (Ca2+) signalling has been characterized as a process that coordinates the inputs of various extracellular stimuli and triggers, or fine-tunes, a vast repertoire of cellular functions1,2(TIMELINE). The initial concept that Ca2+ ions control physiological events goes back to the seminal (and serendipitous) observation by Ringer et al. in 1883 that addition of Ca2+ to the perfusion buffer of isolated hearts triggered their contraction3. Increases in Ca2+ levels can be highly localized (for example, at the synaptic region, the secretory pole of an exocrine cell or the site ofcell–cell interaction of a lymphocyte with an antigenpresenting cell (which is called the immunologica l synapse). Alternatively, local changes in intracellular Ca2+ concentration ([Ca2+]c) can diffuse across the cell as a wave and elicit an effect at a distant site. Moreover, in most cell types the increases in [Ca2+]c are oscillatory 4, and the frequency of each [Ca2+]c oscillation (defined as‘temporal’ Ca2+ signature) is differentially decoded by the cell5,6. This spatiotemporal complexity in the regulation of [Ca2+]c relies on two key requirements. The first is the cooperation of two different sources of Ca2+ in the generation of the [Ca2+]c rise: the extracellular medium, a virtually unlimited reservoir with a [Ca2+] of ~1 mM, and intracellular pools (known as Ca2+ stores, which are endowedwith a [Ca2+] >100 μM) that allow rapid release through store-resident channels7–9. Although recent work has highlighted a role also for other membranebound compartments (such as the Golgi apparatus10, endosomes and lysosomes11), the most important intracellular stores are the endoplasmic reticulum (ER) and its specialized counterpart in muscle cells, the sarcoplasmic reticulum. The secondrequirement for carefully orchestrating [Ca2+]c is the existence of a broad range of

molecules that generate and decode [Ca2+]c variations and their defined positioning within the cell12. Thus, pumps, channels and buffering proteins finely tune the spatiotemporal pattern of [Ca2+]c rises, and targets that are located both in the cytoplasm and in different intracellular organelles sense [Ca2+]c...