Hypoxia-induced alteration of mitochondrial genes in cardiomyocytes: role of Bnip3 and Pdk1.

Abstract

The hypoxic conditions induced by reduced blood flow decreases oxygen availability in target tissues. Cellular hypoxia leads to mitochondrial dysfunction, decreased energy production, and increased production of reactive oxygen species. To determine the alteration in expression of mitochondrial genes after hypoxia in cardiomyocytes, we developed a rodent mitochondrial gene chip (RoMitoChip). The chip had 1088 probe sets including 46 probe sets representing 37 mouse mitochondrial DNA transcripts and the remaining probe sets representing mouse nuclear genes contributing to the mitochondrial structure and function. Mouse cardiomyocytes isolated from neonatal C57BL/6 mice that were subjected to hypoxia (1% oxygen) for different time intervals demonstrated a dichotomy in the expression profile of tRNA and mRNA transcripts. We report a total of 483 signature genes that were altered by hypoxia in the cardiac myocytes and related to mitochondrial structure and function. This includes 23 transcripts on mitochondrial DNA. Pathway analysis demonstrated predominant changes in the expression of genes involved in oxidative phosphorylation, glucose and fatty acid metabolism, and apoptosis. The most upregulated genes after 24 h of hypoxia included hypoxia-inducible factor 1, alpha subunit, inducible genes Bnip3, Pdk1, and Aldoc. Whereas Bnip3 is important in the cardiomyocyte death pathway, Pdk1 enzyme is critical in conserving mitochondrial function by diverting metabolic intermediates to glycolysis. This study identifies the participation of two important pathways, cell death and glycolytic, and two key proteins, Bnip3 and Pdk1, playing critical roles in these pathways in cardiomyocytes after severe hypoxia.

• Authors: Bixi Jian, Deli Wang, Dongquan Chen, Joachim Voss, Irshad Chaudry, Raghavan Raju
• Journal: Shock (Augusta, Ga.) (Shock) Vol. 34 Issue 2 Pg. 169-75 (Aug 2010) ISSN: 1540-0514 [Electronic] United States
• PMID: 20160671 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BNip3 protein, mouse
• DNA, Mitochondrial
• Membrane Proteins
• Mitochondrial Proteins
• Pdk1 protein, mouse
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• RNA, Messenger
• Protein Serine-Threonine Kinases

Topics

• Animals
• DNA, Mitochondrial (drug effects)
• Gene Expression Profiling
• Glycolysis (drug effects, physiology)
• Hypoxia (physiopathology)
• Membrane Proteins (physiology)
• Mice
• Mice, Inbred C57BL
• Mitochondrial Proteins (physiology)
• Myocytes, Cardiac (metabolism)
• Protein Serine-Threonine Kinases (physiology)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• RNA, Messenger (metabolism)