scholarly journals Protection from inactivation of the adenine nucleotide translocator during hypoglycaemia-induced apoptosis by mitochondrial phospholipid hydroperoxide glutathione peroxidase

2003 ◽  
Vol 371 (3) ◽  
pp. 799-809 ◽  
Author(s):  
Hirotaka IMAI ◽  
Tomoko KOUMURA ◽  
Ryo NAKAJIMA ◽  
Kazuhiro NOMURA ◽  
Yasuhito NAKAGAWA
Keyword(s):  
Glutathione Peroxidase ◽  
Adenine Nucleotide ◽  
Control Level ◽  
Permeability Transition ◽  
Adenine Nucleotide Translocator ◽  
Phospholipid Hydroperoxide Glutathione Peroxidase ◽  
Phospholipid Hydroperoxide ◽  
Cyt C ◽  
Permeability Transition Pores ◽  
Induced Apoptosis

We demonstrated that mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx) first suppressed the dissociation of cytochrome c (cyt c) from cardiolipin (CL) in mitochondrial inner membranes and then apoptosis caused by the hypoglycaemia by the prevention of peroxidation of CL [Nomura, Imai, Koumura, Arai and Nakagawa (1999) J. Biol. Chem. 274, 29294–29302; Nomura, Imai, Koumura, Kobayashi and Nakagawa (2000) Biochem. J. 351, 183–193]. The present study shows the involvement of peroxidation of CL in the inactivation of adenine nucleotide translocator (ANT) and the opening of permeability transition pores by using the system of ANT-reconstituted liposome and isolated mitochondria. ANT activity appeared in dioleoyl phosphatidylcholine proteoliposome containing 10% (mol/mol) CL or phosphatidylglycerol (PG), but not other classes of phospholipids. ANT activity was competitively inhibited by the addition of cardiolipin hydroperoxide (CLOOH) in reconstituted liposomes containing CL. However, phosphatidylcholine hydroperoxide failed to inactivate the activity of ANT. The activity of ANT in reconstituted liposomes, including CLOOH, recovered when CLOOH in reconstituted liposome was reduced to hydroxycardiolipin by incubation with PHGPx. The activity of ANT was determined in rat basophil leukaemia RBL2H3 cells after their exposure to 2-deoxyglucose. ANT activity decreased to 50% of the control level by 4 h in response to apoptosis. In parallel, cyt c and apoptosis-inducing factor (AIF) were released from mitochondria. Suppression of the accumulation of CLOOH by overexpression of PHGPx in mitochondria effectively prevented the inactivation of ANT, the opening of permeability transition pores and the release of cyt c and AIF from mitochondria in hypoglycaemia-induced apoptotic cells. These findings suggest that mitochondrial PHGPx might be involved in the modulation of the activity of ANT and the opening of pores for the release of cyt c via the modulation of levels of CLOOH in the mitochondria.

Mitochondrial phospholipid hydroperoxide glutathione peroxidase inhibits the release of cytochrome c from mitochondria by suppressing the peroxidation of cardiolipin in hypoglycaemia-induced apoptosis

2000 ◽  
Vol 351 (1) ◽  
pp. 183-193 ◽  
Author(s):  
Kazuhiro NOMURA ◽  
Hirotaka IMAI ◽  
Tomoko KOUMURA ◽  
Toshihide KOBAYASHI ◽  
Yasuhito NAKAGAWA
Keyword(s):  
Cytochrome C ◽  
Glutathione Peroxidase ◽  
Acridine Orange ◽  
Phospholipid Hydroperoxide Glutathione Peroxidase ◽  
Primary Event ◽  
Phospholipid Hydroperoxide ◽  
Cyt C ◽  
Mitochondrial Lipid ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

Cytochrome c (cyt. c) is a proapoptotic factor that binds preferentially to cardiolipin (CL), a mitochondrial lipid, but not to cardiolipin hydroperoxide (CL-OOH). Cyt. c that had bound to CL liposomes was liberated on peroxidation of the liposomes by a radical. The generation of CL-OOH in mitochondria occurred before the release of cyt. c in rat basophile leukaemia (RBL)2H3 cells that had been induced to undergo apoptosis by exposure to hypoglycaemia with 2-deoxyglucose (2DG). The amount of cyt. c bound to CL prepared from the mitochondria of 2DG-treated cells was lower than that of untreated cells. The release of cyt. c was completely suppressed when the production of CL-OOH in mitochondria was inhibited by the overexpression of mitochondrial phospholipid hydroperoxide glutathione peroxidase (PHGPx). The fluorescence from CL-labelling dye (10-N-nonyl Acridine Orange) decreased on the induction of apoptosis by 2DG. However, no decrease in fluorescence was observed in PHGPx-overexpressing cells. Cyt. c was released from mitochondria that had been isolated from control cells on peroxidation by t-butylhydroperoxide, but no similar liberation of cyt. c from mitochondria isolated from mitochondrial PHGPx-overexpressing cells was observed. These findings suggest that the generation of CL-OOH in mitochondria might be a primary event that triggers the release of cyt. c from mitochondria in the apoptotic process in which mitochondrial PHGPx participates as an anti-apoptotic factor by preventing the formation of CL-OOH.

Prevention of geranylgeranoic acid-induced apoptosis by phospholipid hydroperoxide glutathione peroxidase gene

2005 ◽  
Vol 97 (1) ◽  
pp. 178-187 ◽  
Author(s):  
Yoshihiro Shidoji ◽  
Kyoko Okamoto ◽  
Yasutoshi Muto ◽  
Sadaaki Komura ◽  
Nobuko Ohishi ◽  
...  
Keyword(s):  
Glutathione Peroxidase ◽  
Phospholipid Hydroperoxide Glutathione Peroxidase ◽  
Peroxidase Gene ◽  
Phospholipid Hydroperoxide ◽  
Induced Apoptosis
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