Mitochondria and cell signalling

Abstract

Commentary 807Introduction Mitochondria are often termed the 'powerhouse' of the cell for good reason. Not only do mitochondria have a key role in ATP synthesis, but they are also crucial for various other cellular processes, including fatty acid synthesis, Ca 2+ homeostasis and the biogenesis of haem and iron-sulphur proteins. Given this plethora of functions, it is perhaps not surprising that mitochondria are also heavily integrated into the cell signalling circuitry. The traditional view of mitochondria in signalling is that they represent signalling effectors, for example, by enabling the upregulation of ATP synthesis in response to growthpromoting stimuli. However, more recent evidence demonstrates that mitochondria also actively participate in numerous biological processes by acting as initiators and transducers of cell signalling. In general, mitochondria regulate cell signalling through two means: serving as physical platforms on which protein-protein signalling interactions occur, and by regulating the levels of intracellular signalling molecules, including Ca 2+ and reactive oxygen species (ROS). Consequently, mitochondria have been implicated in the regulation of various processes, including growth factor signalling, differentiation and hypoxic stress responses, which are discussed elsewhere (Antico Arciuch et al., 2012;Chandel, 2010;Finkel, 2011;Gunter et al., 2004). In this Commentary, we focus on the signalling roles that mitochondria have in cell death, innate immunity and autophagy. These areas are collectively discussed because of their numerous interconnections. For example, cell death acts as a firstline defence against invading pathogens and serves to alert the innate immune system to infection, whereas autophagy generally acts as a pro-survival mechanism and controls innate immunity at multiple levels, such as through the regulation of pro-inflammatory cytokine production. Mitochondrial regulation of cell death signallingProgrammed cell death is required for proper development and tissue homeostasis in all multicellular organisms, and its deregulation contributes to various diseases including cancer and neurodegeneration. The predominant form of programmed cell death is apoptosis, a process that requires activation of the caspase proteases. Once activated, caspases cleave several hundred different proteins, leading to rapid apoptotic cell death (Taylor et al., 2008). This is associated with characteristic morphological changes, including plasma membrane blebbing and nuclear condensation. Mitochondria are involved in regulating caspase activity and apoptosis in all multicellular organisms to varying degrees and through different mechanisms (Oberst et al., 2008). For example, in the nematode Caenorhabditis elegans, mitochondria serve a non-essential role during apoptosis because, even though they act as a platform for key apoptotic signalling proteins, these proteins do not have to be localised to mitochondria per se in order to regulate apoptosis (Tan et al., 2007). In other organisms, mitoch...

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