scholarly journals Mitochondrial Dysfunction Induced by a Cytotoxic Adenine Dinucleotide Produced by ADP-ribosyl Cyclases from cADPR

2006 ◽  
Vol 282 (7) ◽  
pp. 5045-5052 ◽  
Author(s):  
Santina Bruzzone ◽  
Giuliano Dodoni ◽  
Nina Kaludercic ◽  
Giovanna Basile ◽  
Enrico Millo ◽  
...  
Keyword(s):  
Relative Concentration ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Cell Types ◽  
Proton Gradient ◽  
Life And Death ◽  
Adp Ribosyl Cyclase ◽  
Cell Life ◽  
Cyclic Adp Ribose ◽  
Permeability Transition Pore Complex

ADP-ribosyl cyclases were previously shown to produce three new adenine dinucleotides, P1,P2 diadenosine 5′-diphosphate (Ap2A) and two isomers thereof (P18 and P24), from cyclic ADP-ribose (cADPR) and adenine (Basile, G., Taglialatela-Scafati, O., Damonte, G., Armirotti, A., Bruzzone, S., Guida, L., Franco, L., Usai, C., Fattorusso, E., De Flora, A., and Zocchi, E. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 14509-14514). The Ap2A isomer P24, containing an unusual C1′-N3 N-glycosidic bond, is shown here to affect mitochondrial function through (i) opening of the permeability transition pore complex (and consequent proton gradient dissipation) and (ii) inhibition of Complex I of the respiratory chain. Whereas proton gradient dissipation is dependent upon the extracellular Ca2+ influx triggered by P24, the effect on oxygen consumption is Ca2+ independent. The proton gradient dissipation induces apoptosis in HeLa cells and thus appears to be responsible for the already described potent cytotoxic effect of P24 on several human cell types. The other products of ADP-ribosyl cyclase activity, Ap2A and cADPR, antagonize P24-induced proton gradient dissipation and cytotoxicity, suggesting that the relative concentration of P24, cADPR, and Ap2A in cyclase-positive cells may affect the balance between cell life and death.

The permeability transition pore complex: another view

Biochimie ◽  
2002 ◽  
Vol 84 (2-3) ◽  
pp. 153-166 ◽  
Author(s):  
Andrew P Halestrap ◽  
Gavin P McStay ◽  
Samantha J Clarke
Keyword(s):  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Permeability Transition Pore Complex

A role for mitochondrial aquaporins in cellular life-and-death decisions?

2006 ◽  
Vol 291 (2) ◽  
pp. C195-C202 ◽  
Author(s):  
Wing-Kee Lee ◽  
Frank Thévenod
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Water Movement ◽  
Apoptotic Cell ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Swelling ◽  
Inner Mitochondrial Membrane ◽  
Osmotic Swelling ◽  
Life And Death

Mitochondria dominate the process of life-and-death decisions of the cell. Continuous generation of ATP is essential for cell sustenance, but, on the other hand, mitochondria play a central role in the orchestra of events that lead to apoptotic cell death. Changes of mitochondrial volume contribute to the modulation of physiological mitochondrial function, and several ion permeability pathways located in the inner mitochondrial membrane have been implicated in the mediation of physiological swelling-contraction reactions, such as the K+ cycle. However, the channels and transporters involved in these processes have not yet been identified. Osmotic swelling is also one of the fundamental characteristics exhibited by mitochondria in pathological situations, which activates downstream cascades, culminating in apoptosis. The permeability transition pore has long been postulated to be the primary mediator for water movement in mitochondrial swelling during cell death, but its molecular identity remains obscure. Inevitably, accumulating evidence shows that mitochondrial swelling induced by apoptotic stimuli can also occur independently of permeability transition pore activation. Recently, a novel mechanism for osmotic swelling of mitochondria has been described. Aquaporin-8 and -9 channels have been identified in the inner mitochondrial membrane of various tissues, including the kidney, liver, and brain, where they may mediate water transport associated with physiological volume changes, contribute to the transport of metabolic substrates, and/or participate in osmotic swelling induced by apoptotic stimuli. Hence, the recent discovery that aquaporins are expressed in mitochondria opens up new areas of investigation in health and disease.

scholarly journals Mitochondria in Neurodegeneration: Bioenergetic Function in Cell Life and Death

1999 ◽  
Vol 19 (3) ◽  
pp. 231-245 ◽  
Author(s):  
Anne N. Murphy ◽  
Gary Fiskum ◽  
M. Flint Beal
Keyword(s):  
Cell Death ◽  
Reactive Oxygen Species Generation ◽  
Decisive Role ◽  
Permeability Transition ◽  
Oxygen Species ◽  
Therapeutic Approaches ◽  
Life And Death ◽  
Biochemical Pathways ◽  
Cell Life ◽  
Mitochondrial Functions

The biochemical pathways to cell death in chronic and acute forms of neurodegeneration are poorly understood, limiting the ability to develop effective therapeutic approaches. As details of the apoptotic and necrotic pathways have been revealed, an appreciation for the decisive role that mitochondria play in life-death decisions for the cell has grown. As a result, the need has arisen to reevaluate the significance to cell viability of mitochondrial Ca2+ sequestration, reactive oxygen species generation, and the membrane permeability transition. This review provides basic information on these mitochondrial functions as they relate to control over cell death.

Sign in / Sign up

Export Citation Format

Share Document