The survival effect of mitochondrial Higd-1a is associated with suppression of cytochrome C release and prevention of caspase activation.
Biochim Biophys Acta
; 1813(12): 2088-98, 2011 Dec.
Article
in En
| MEDLINE
| ID: mdl-21856340
ABSTRACT
Higd-1a (hypoxia induced gene domain family-1a) is a mitochondrial inner membrane protein with a conformation of N-terminal outside-C-terminal outside and loop inside. There are four Higd genes, Higd-1a, -1b, -1c and -2a, in the mouse. Higd-1a and -2a are expressed primarily in the brain, heart, kidney and leukocytes. HIF (hypoxia-inducible factor) overexpression induced the endogenous expression and promoter activity of Higd-1a. Mutation of the HRE (hypoxia-response element) site at -32bp in the Higd-1a promoter reduced the promoter activity, suggesting that transcription of Higd-1a is regulated by binding of the transcription factor HIF to the HRE. Higd-1a promoted cell survival under hypoxia. RAW264.7 cells stably transfected with Higd-1a underwent less apoptosis than control cells in a hypoxic condition, and hypoxia-induced apoptosis was strongly enhanced when endogenous Higd-1a was silenced by siRNA. The survival effect of Higd-1a was completely abolished by deletion of the 26 N-terminal amino acids, and we showed that Higd-1a increased survival by inhibiting cytochrome C release and reducing the activities of caspases. However, expression of Bcl-2, Bax, Bad, and BNIP3 and translocation of AIF were unaffected under the same conditions. Higd-2a also enhanced cell survival under hypoxia. Cells transfected with Higd-2a underwent less apoptosis than control cells in hypoxic conditions, and hypoxia-induced apoptosis increased when endogenous Higd-2a was depleted. Together these observations indicate that Higd-1a is induced by hypoxia in a HIF-dependent manner and its anti-apoptotic effect results from inhibiting cytochrome C release and reducing caspase activities.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Apoptosis
/
Caspases
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Mitochondrial Proteins
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Cytochromes c
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins
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Mitochondria
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Biochim Biophys Acta
Year:
2011
Document type:
Article