Bax-induced cell death in yeast depends on mitochondrial lipid oxidation.
The oxidant function of pro-apoptotic protein Bax was investigated through heterologous expression in yeast. Direct measurements of fatty acid content show that Bax-expression induces oxidation of mitochondrial lipids. This effect is prevented by the coexpression of Bcl-xL. The oxidation actually could be followed on isolated mitochondria as respiration-induced peroxidation of polyunsaturated cis-parinaric acid and on whole cells as the increase in the amount of thiobarbituric acid-reactive products. Treatments that increase the unsaturation ratio of lipids, making them more sensitive to oxidation, increase kinetics of Bax-induced death. Conversely, inhibitors of lipid oxidation and treatments that decrease the unsaturation ratio of fatty acids decrease kinetics of Bax-induced death. Taken together, these results show that Bax-induced mitochondrial lipid oxidation is relevant to Bax-induced cell death. Conversely, lipid oxidation is poorly related to the massive Bax-induced superoxide and hydrogen peroxide accumulation, which occurs at the same time, as chemical or enzymatic scavenging of ROS does not prevent lipid oxidation nor has any effects on kinetics of Bax-induced cell death. Whatever the origin of mitochondrial lipid oxidation, these data show that it represents a major step in the cascade of events leading to Bax-induced cell death. These results are discussed in the light of the role of lipid oxidation both in mammalian apoptosis and in other forms of cell death in other organisms.
Priault
Muriel
M
UMR5095 C.N.R.S./Université de Bordeaux 2, Bordeaux, France; UMR5544 C.N.R.S./Université de Bordeaux 2, Bordeaux, France.
Bessoule
Jean-Jacques
JJ
Grelaud-Coq
Angela
A
Camougrand
Nadine
N
Manon
Stéphen
S
D017209:Apoptosis; D016923:Cell Death; D005227:Fatty Acids / Q000378:metabolism; D005838:Genotype; D007700:Kinetics; D050356:Lipid Metabolism; D008928:Mitochondria / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species; D013104:Spheroplasts / Q000378:metabolism; D013482:Superoxide Dismutase; D017392:Thiobarbituric Acid Reactive Substances; D013997:Time Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
D005227:Fatty Acids; D010743:Phospholipids; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D013482:Superoxide Dismutase; D010100:Oxygen