HSP72 inhibits apoptosis-inducing factor release in ATP-depleted renal epithelial cells.
Inhibition of the mitochondrial release and nuclear translocation of apoptosis-inducing factor (AIF) by heat stress protein (HSP)72 may ameliorate apoptosis in renal epithelial cells exposed to a metabolic inhibitor. To evaluate this hypothesis, cells were transiently exposed to 5 mM sodium cyanide in the absence of medium glucose, a maneuver known to induce apoptosis. ATP depletion for 1-2 h resulted in the progressive accumulation of mitochondrial AIF in the cytosol of samples obtained by selectively permeabilizing the plasma membrane with digitonin. During recovery from ATP depletion, time-dependent nuclear AIF accumulation (but not cytochrome c, an F0F1 ATP synthase subunit, or talin) was observed in isolated nuclei. Nuclear AIF accumulation was associated with peripheral chromatin condensation and DNA degradation. Prior heat stress (HS) significantly reduced AIF leakage into the cytosol, decreased nuclear accumulation of AIF, and inhibited DNA degradation. HS also increased the interaction between AIF and HSP72 detected by immunoprecipitation. In ATP depleted cells, selective overexpression of human HSP72 reduced the leakage of mitochondrial AIF in a dose-dependent manner (r = 0.997). This study suggests that mitochondrial membrane injury and subsequent AIF release contribute to nuclear injury and apoptosis in ATP-depleted renal cells. HSP72, an antiapoptotic protein, inhibits cell injury in part by preventing mitochondrial AIF release and perhaps by decreasing its nuclear accumulation.
Ruchalski
Kathleen
K
Evans Biomedical Research Center, Renal Section, Rm. 547, 650 Albany St., Boston, MA 02118-2518, USA.
Mao
Haiping
H
Singh
Satish K
SK
Wang
Yihan
Y
Mosser
Dick D
DD
Li
Fanghong
F
Schwartz
John H
JH
Borkan
Steven C
SC
D000255:Adenosine Triphosphate / Q000172:deficiency; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor; D002467:Cell Nucleus / Q000378:metabolism; D053938:DNA Fragmentation / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D005420:Flavoproteins / Q000378:metabolism*; D050884:HSP72 Heat-Shock Proteins; D018882:Heat Stress Disorders / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D018869:Heat-Shock Response / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology / Q000502:physiology; D008565:Membrane Proteins / Q000378:metabolism*; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009893:Opossums; D011233:Precipitin Tests
D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D050884:HSP72 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008565:Membrane Proteins; D000255:Adenosine Triphosphate