Mitochondria, calcium and pro-apoptotic proteins as mediators in cell death signaling

Abstract

Cellular Ca 2+ signals are crucial in the control of most physiological processes, cell injury and programmed cell death through the regulation of a number of Ca 2+ -dependent enzymes such as phospholipases, proteases, and nucleases. Mitochondria along with the endoplasmic reticulum play pivotal roles in regulating intracellular Ca 2+ content. Mitochondria are endowed with multiple Ca 2+ transport mechanisms by which they take up and release Ca 2+ across their inner membrane. During cellular Ca 2+ overload, mitochondria take up cytosolic Ca 2+ , which in turn induces opening of permeability transition pores and disrupts the mitochondrial membrane potential (Dy m ). The collapse of Dy m along with the release of cytochrome c from mitochondria is followed by the activation of caspases, nuclear fragmentation and cell death. Members of the Bcl-2 family are a group of proteins that play important roles in apoptosis regulation. Members of this family appear to differentially regulate intracellular Ca 2+ level. Translocation of Bax, an apoptotic signaling protein, from the cytosol to the mitochondrial membrane is another step in this apoptosis signaling pathway. Correspondence

KR-32570, a novel Na+/H+ exchanger-1 inhibitor, attenuates hypoxia-induced cell death through inhibition of intracellular Ca2+ overload and mitochondrial death pathway in H9c2 cells

“…This uptake is driven by the negative potential difference across the mitochondrial membrane, which is maintained by proton extrusion from the electron transport chain (Parekh, 2003), allowing mitochondria to function as buffers against cytosolic Ca 2+ overload (Parekh, 2003). During myocardial hypoxia, cytosolic Ca 2+ is elevated as a result of NHE-1 and subsequent NCX activation, and this increased cytosolic Ca 2+ is taken up by mitochondria (Smaili et al, 2003). Because electron transport is inhibited during hypoxia, increased mitochondrial Ca 2+ leads to a fall in of ΔΨ m , and permeability transition pore opening (Orrenius et al, 2003).…”

Sepsis, mitochondrial failure and multiple organ dysfunction

“…As is amply demonstrated, cellular hypoxia causes an increase of free radicals, which increases the already high state of oxidative stress and leads to the entry of calcium to the endoplasmic reticulum and mitochondria, causing the release of cytochrome c and the induction of cellular death. Finally, mitochondria failure with the consequent energy de cit does not allow for normal cellular metabolism [5]. With ischemia, the accumulation of intracellular calcium leads to an increase of AMPc and vascular endothelium injury [6].…”

“…Subsequently, through the enzyme complex of pyruvate dehydrogenase (PDH), NAD (nicotinamine adenine dinucleotide) and coenzyme A, acetylCoA is formed within the mitochondria. Acetyl-CoA enters the Krebs cycle to produce energy in the form of GTP, which is used to promote the synthesis of ATP [5]. A large number of reactive species are produced as a result of this energy metaboDurán-Bedolla et al Sepsis, mitochondrial failure and MOD lism.…”

Bax affects intracellular Ca2+ stores and induces Ca2+ wave propagation

“…1,32 According to several lines of evidence, different hypotheses were drawn to discuss the permeabilization induced by apoptotic members of Bcl-2 proteins. The ability of Bax to form homo-or heterodimers 33 could induce Bax to form oligomers when associated with mitochondrial membranes 31,34 or mitochondrial contact sites.…”