Mammalian life span can be controlled by p66Shc protein through regulation of cellular response to oxidative stress. We investigated age-related changes in the amount of p66Shc and its ...Ser36-phosphorylated form in various mouse organs and tissues and correlated it with the level of antioxidant enzymes. Comparing to the newborn, in adult 6-month-old mice, the level of p66Shc was increased particularly in liver, lungs, skin and diaphragm. In older animals the level of p66Shc decreased while signaling pathway responsible for Ser36 phosphorylation of p66Shc protein seemed to be continually enhanced. The amount of p66Shc phosphorylated at Ser36, significantly increased with age, resulted in higher free radical production and, in consequence accumulation of damages caused by free radicals. The increased amount of Ser36-phosphorylated p66Shc in livers of 12- and 23-month-old mice was correlated with the decreased level of antioxidant enzymes. Moreover, we found that p66Shc is a resident of mitochondria- and plasma membrane-associated membranes and that its level there depends on the age of animal.
Mitochondrial dynamics and Ca2+ signaling Szabadkai, G; Simoni, A M; Bianchi, K ...
Biochimica et biophysica acta,
2006 May-Jun, 2006-05-00, Letnik:
1763, Številka:
5-6
Journal Article
Recenzirano
Odprti dostop
Recent data shed light on two novel aspects of the mitochondria-Ca2+ liaison. First, it was extensively investigated how Ca2+ handling is controlled by mitochondrial shape, and positioning; a ...playground also of cell death and survival regulation. On the other hand, significant progress has been made to explore how intra- and near-mitochondrial Ca2+ signals modify mitochondrial morphology and cellular distribution. Here, we shortly summarize these advances and provide a model of Ca2+-mitochondria interactions.
Transmembrane BAX inhibitor motif-containing (TMBIM)-6, also known as BAX-inhibitor 1 (BI-1), is an anti-apoptotic protein that belongs to a putative family of highly conserved and poorly ...characterized genes. Here we report the function of TMBIM3/GRINA in the control of cell death by endoplasmic reticulum (ER) stress. Tmbim3 mRNA levels are strongly upregulated in cellular and animal models of ER stress, controlled by the PERK signaling branch of the unfolded protein response. TMBIM3/GRINA synergies with TMBIM6/BI-1 in the modulation of ER calcium homeostasis and apoptosis, associated with physical interactions with inositol trisphosphate receptors. Loss-of-function studies in D. melanogaster demonstrated that TMBIM3/GRINA and TMBIM6/BI-1 have synergistic activities against ER stress in vivo. Similarly, manipulation of TMBIM3/GRINA levels in zebrafish embryos revealed an essential role in the control of apoptosis during neuronal development and in experimental models of ER stress. These findings suggest the existence of a conserved group of functionally related cell death regulators across species beyond the BCL-2 family of proteins operating at the ER membrane.
Department of Experimental and Diagnostic Medicine and Interdisciplinary Center for the Study of Inflammation, University of Ferrara, Ferrara; and Department of Biomedical Sciences, National Research ...Council Institute of Neuroscience, and Venetian Institute of Molecular Medicine, University of Padua, Padua, Italy
Calcium ions are ubiquitous and versatile signaling molecules, capable of decoding a variety of extracellular stimuli (hormones, neurotransmitters, growth factors, etc.) into markedly different intracellular actions, ranging from contraction to secretion, from proliferation to cell death. The key to this pleiotropic role is the complex spatiotemporal organization of the Ca 2+ rise evoked by extracellular agonists, which allows selected effectors to be recruited and specific actions to be initiated. In this review, we discuss the structural and functional bases that generate the subcellular heterogeneity in cellular Ca 2+ levels at rest and under stimulation. This complex choreography requires the concerted action of many different players; the central role is, of course, that of the calcium ion, with the main supporting characters being all the entities responsible for moving Ca 2+ between different compartments, while the cellular architecture provides a determining framework within which all the players have their exits and their entrances. In particular, we concentrate on the molecular mechanisms that lead to the generation of cytoplasmic Ca 2+ microdomains, focusing on their different subcellular location, mechanism of generation, and functional role.
Address for reprint requests and other correspondence: Address for reprint requests and other correspondence: T. Pozzan, Dept. of Biomedical Sciences, Viale G. Colombo 3, 35121 Padua, Italy (e-mail: tullio.pozzan{at}unipd.it )
Calcium is the most abundant cation in vertebrates, and the function of calcium2plus is so important for the survival of the organism that evolution has developed multiple ways to take advantage of ...the enormous calcium2plus deposits in the bones and to avoid any risk of calcium2plus deprivation. The molecular and cellular physiology of these intracellular calcium stores are examined.
Despite advanced knowledge on the genetic basis of oxidative phosphorylation-related diseases, the molecular and/or cellular determinants for tissue-specific dysfunction are not completely ...understood. Here, we report the cellular events associated with mitochondrial respiratory Complex II deficiency occurring before cell death. Mutation or chronic inhibition of Complex II determined a large increase of basal and agonist-evoked Ca(2+) signals in the cytosol and the mitochondria, in parallel with mitochondrial dysfunction characterized by membrane potential (Δψ(mit)) loss, ATP reduction and increased reactive oxygen species production. Cytosolic and mitochondrial Ca(2+) overload are linked to increased endoplasmic reticulum (ER) Ca(2+) leakage, and to SERCA2b and PMCA proteasome-dependent degradation. Increased Ca(2+)(mit) is also contributed by decreased mitochondrial motility and increased ER-mitochondria contact sites. Interestingly, increased intracellular Ca(2+) activated on the one hand a compensatory Ca(2+)-dependent glycolytic ATP production and determined on the second hand mitochondrial pathology. These results revealed the primary function for Ca(2+) signalling in the control of mitochondrial dysfunction and cellular bioenergetics outcomes linked to respiratory chain Complex II deficiency.
Bcl-2 is a prosurvival factor that reportedly prevents the nonspecific permeabilization of mitochondrial membranes, yet enhances specific ADP/ATP exchange by these organelles. Here, we show that ...Bcl-2 enhances the ADP/ATP exchange in proteoliposomes containing the purified adenine nucleotide translocase (ANT) in isolated mitochondria and mitoplasts, as well as in intact cells in which mitochondrial matrix ATP was monitored continuously using a specific luciferase-based assay system. Conversely, Bax, which displaces Bcl-2 from ANT in apoptotic cells, inhibits ADP/ATP exchange through a direct action on ANT. The Bax-mediated inhibition of ADP/ATP exchange can be separated from Bax-stimulated formation of nonspecific pores by ANT. Chemotherapy-induced apoptosis caused an inhibition of ANT activity, which preceded the loss of the mitochondrial transmembrane potential and could be prevented by overexpression of Bcl-2. These data are compatible with a model of mitochondrial apoptosis regulation in which ANT interacts with either Bax or Bcl-2, which both influence ANT function in opposing manners. Bcl-2 would maintain the translocase activity at high levels, whereas Bax would inhibit the translocase function of ANT.
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