RGD Reference Report - Adaptability to hypobaric hypoxia is facilitated through mitochondrial bioenergetics: an in vivo study. - Rat Genome Database

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Adaptability to hypobaric hypoxia is facilitated through mitochondrial bioenergetics: an in vivo study.

Authors: Chitra, Loganathan  Boopathy, Rathanam 
Citation: Chitra L and Boopathy R, Br J Pharmacol. 2013 Jul;169(5):1035-47. doi: 10.1111/bph.12179.
RGD ID: 12738217
Pubmed: PMID:23517027   (View Abstract at PubMed)
PMCID: PMC3696327   (View Article at PubMed Central)
DOI: DOI:10.1111/bph.12179   (Journal Full-text)


BACKGROUND AND PURPOSE: High-altitude pulmonary oedema (HAPE) experienced under high-altitude conditions is attributed to mitochondrial redox distress. Hence, hypobaric hypoxia (HH)-induced alteration in expression of mitochondrial biogenesis and dynamics genes was determined in rat lung. Further, such alteration was correlated with expression of mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (mtOXPHOS) genes. The prophylactic effect of dexamethasone (DEX) in counteracting the HH-induced mitochondrial distress was used as control to understand adaptation to high-altitude exposure.
EXPERIMENTAL APPROACH: Rats pretreated with DEX were exposed to normobaric normoxia (NN) or HH. HH-induced injury was assessed as an increase in lung water content, tissue damage and oxidant generation. Mitochondrial number, mtDNA content and mtOXPHOS activities were measured to determine mitochondrial function. The expression of mitochondrial biogenesis, dynamics and mtOXPHOS genes was studied.
KEY RESULTS: HH-induced lung injury was associated with decreased mitochondrial number, mtDNA content and mtOXPHOS activities. HH exposure decreased the nuclear gene oestrogen-related receptor-α (ERRα), which interacts with PPAR-γ coactivator-1α (PGC-1α) in controlling mitochondrial metabolism. Consequently, mtOXPHOS transcripts are repressed under HH. Further, HH modulated mitochondrial dynamics by decreasing mitofusin 2 (Mfn2) and augmenting fission 1 (Fis1) and dynamin-related protein 1 (Drp1) expression. Nevertheless, DEX treatment under NN (i.e. adaptation to HH) did not affect mitochondrial biogenesis and dynamics, but increased mtOXPHOS transcripts. Further, mtOXPHOS activities increased together with reduced oxidant generation. Also, DEX pretreatment normalized ERRα along with mitochondrial dynamics genes and increased mtOXPHOS transcripts to elicit the mitochondrial function under HH.
CONCLUSIONS AND IMPLICATIONS: HH stress (HAPE)-mediated mitochondrial dysfunction is due to repressed ERRα and mtOXPHOS transcripts. Thus, ERRα-mediated protection of mitochondrial bioenergetics might be the likely candidate required for lung adaptation to HH.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Pulmonary Edema of Mountaineers  ISODnm1l (Rattus norvegicus)12738217; 12738217mRNA:increased expression:lung (rat)RGD 
Pulmonary Edema of Mountaineers  IEP 12738217; 12738217mRNA:increased expression:lung (rat)RGD 
Pulmonary Edema of Mountaineers  ISOFis1 (Rattus norvegicus)12738217; 12738217mRNA:increased expression:lung (rat)RGD 
Pulmonary Edema of Mountaineers  ISOMfn2 (Rattus norvegicus)12738217; 12738217mRNA:decreased expression:lung (rat)RGD 
Pulmonary Edema of Mountaineers  IEP 12738217mRNA:decreased expression:lung (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Dnm1l  (dynamin 1-like)
Fis1  (fission, mitochondrial 1)
Mfn2  (mitofusin 2)

Genes (Mus musculus)
Dnm1l  (dynamin 1-like)
Fis1  (fission, mitochondrial 1)
Mfn2  (mitofusin 2)

Genes (Homo sapiens)
DNM1L  (dynamin 1 like)
FIS1  (fission, mitochondrial 1)
MFN2  (mitofusin 2)


Additional Information