Abstract
In the last few years, a growing bulk of evidences demonstrated that mitochondrial dysfunction might play a prominent role in the pathogenesis of several neurodegenerative disease. Mitochondria are essential organelles involved with oxidative phosphorylation, calcium homeostasis, reactive oxygen species (ROS) management, and programmed cell death (PCD). The convergence on the mitochondria of a number of cell death pathways arising from membrane receptors activation, cytosolic perturbations, nucleus, lysosome, and endoplasmic reticulum results in mitochondrial destabilization. A common consequence of the activation of these death pathways is, indeed, mitochondrial dysfunction and mitochondrial membrane permeabilization (MMP). Mitochondrial membrane destabilization causes the release of components such as cytochrome c and apoptosis inducing factor (AIF) which in turn initiate the caspase-dependent and -independent intrinsic PCD programs. On the other hand, mitochondrial dysfunction leads to oxidative stress, damage to mitochondrial DNA, mitochondrial DNA deletions, altered mitochondrial morphology, alterations in mitochondrial fission and fusion, and ultimately cellular demise.
Besides performing oxidative phosphorylation, mitochondria are able to sense and shape calcium (Ca2+) transients, thus controlling cytosolic Ca2+ signals and Ca2+-dependent protein activity. Indeed, it has been well established for many years that mitochondria have a huge capacity to accumulate calcium. While the physiological significance of this pathway was hotly debated until relatively recently, it is now clear that the ability of mitochondria in calcium handling is an ubiquitous phenomenon described in every cell system in which the issue has been addressed. Therefore, mitochondria are now recognized as one of the main intracellular calcium storing organelles which play a key role in the intracellular calcium signaling.
In this chapter, the molecular mechanisms involved in regulation of mitochondrial calcium cycling both in physiological and in pathological conditions are described. A particular emphasis is devoted to the understanding of the mitochondrial responses occurring in cerebral ischemia and to the discussion of the contribution played by these organelles to tissue damage. Finally, the role of the newly identified mitochondrial proteins in the regulation of mitochondrial calcium dynamics is also explored as a starting point for investigation of new molecular target responsible for mitochondrial dysfunctions leading to cell death.
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Sisalli, M.J., Savoia, C., Scorziello, A. (2012). Mitochondrial Ca2+ Dysregulation During Stroke and Cell Death. In: Li, Y., Zhang, J. (eds) Metal Ion in Stroke. Springer Series in Translational Stroke Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9663-3_3
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