mHGTD-P mediates hypoxic neuronal cell death via the release of apoptosis-inducing factor.
HGTD-P is a pro-apoptotic target protein of hypoxia-inducible factor 1alpha (HIF-1alpha). It localizes to mitochondria and induces the mitochondrial permeability transition through its interaction with voltage dependent anion channels when overexpressed. However, the molecular mechanisms responsible for its induction and its downstream effector molecules required during cell death, especially in neuronal cell death by hypoxia, are largely unknown. We performed this work to elucidate the effects of the pro-apoptotic protein HGTD-P on neuronal cell death induced by hypoxia and to investigate the cell death mechanisms activated during this process. In this report, we show that mouse HGTD-P (mHGTD-P) is transcriptionally increased by hypoxia and that its overexpression triggers neuronal cell death with affected cells displaying shrunken cytoplasm and condensed pyknotic nuclei in a caspase-independent manner. In addition, suppression of endogenous mHGTD-P expression by siRNA rescues neuronal cells from hypoxic injury. Finally, we show that mHGTD-P induces the mitochondrial release of apoptosis-inducing factor into the cytoplasm. Taken together, our data suggest that mHGTD-P participates in caspase-independent hypoxic neuronal cell death. Future studies will be necessary in order to determine whether hypoxia-induced mHGTD-P expression has any relevance in an ischemic animal model or clinical hypoxia-induced disorders.
Cho
Young-Eun
YE
Department of Pathology and Biomedical Research Center for Reactive Oxygen Species, College of Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Ko
Jeong-Hun
JH
Kim
Yong-Jun
YJ
Yim
Ji-Hye
JH
Kim
Su-Mi
SM
Park
Jae-Hoon
JH
D000818:Animals; D051033:Apoptosis Inducing Factor / Q000378:metabolism*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D051033:Apoptosis Inducing Factor; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020169:Caspases