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PMID:22474353

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Citation

Ke, BX, Pepe, S, Grubb, DR, Komen, JC, Laskowski, A, Rodda, FA, Hardman, BM, Pitt, JJ, Ryan, MT, Lazarou, M, Koleff, J, Cheung, MM, Smolich, JJ and Thorburn, DR (2012) Tissue-specific splicing of an Ndufs6 gene-trap insertion generates a mitochondrial complex I deficiency-specific cardiomyopathy. Proc. Natl. Acad. Sci. U.S.A. 109:6165-70

Abstract

Mitochondrial complex I (CI) deficiency is the most common mitochondrial enzyme defect in humans. Treatment of mitochondrial disorders is currently inadequate, emphasizing the need for experimental models. In humans, mutations in the NDUFS6 gene, encoding a CI subunit, cause severe CI deficiency and neonatal death. In this study, we generated a CI-deficient mouse model by knockdown of the Ndufs6 gene using a gene-trap embryonic stem cell line. Ndufs6(gt/gt) mice have essentially complete knockout of the Ndufs6 subunit in heart, resulting in marked CI deficiency. Small amounts of wild-type Ndufs6 mRNA are present in other tissues, apparently due to tissue-specific mRNA splicing, resulting in milder CI defects. Ndufs6(gt/gt) mice are born healthy, attain normal weight and maturity, and are fertile. However, after 4 mo in males and 8 mo in females, Ndufs6(gt/gt) mice are at increased risk of cardiac failure and death. Before overt heart failure, Ndufs6(gt/gt) hearts show decreased ATP synthesis, accumulation of hydroxyacylcarnitine, but not reactive oxygen species (ROS). Ndufs6(gt/gt) mice develop biventricular enlargement by 1 mo, most pronounced in males, with scattered fibrosis and abnormal mitochondrial but normal myofibrillar ultrastructure. Ndufs6(gt/gt) isolated working heart preparations show markedly reduced left ventricular systolic function, cardiac output, and functional work capacity. This reduced energetic and functional capacity is consistent with a known susceptibility of individuals with mitochondrial cardiomyopathy to metabolic crises precipitated by stresses. This model of CI deficiency will facilitate studies of pathogenesis, modifier genes, and testing of therapeutic approaches.

Links

PubMed PMC3341001 Online version:10.1073/pnas.1113987109

Keywords

Adenosine Triphosphate/metabolism; Animals; Animals, Newborn; Blotting, Western; Cardiomyopathies/genetics; Cardiomyopathies/metabolism; Cardiomyopathies/physiopathology; Carnitine/analogs & derivatives; Carnitine/metabolism; Cell Line; Electron Transport Complex I/deficiency; Electron Transport Complex I/genetics; Electron Transport Complex I/metabolism; Female; Gene Expression Profiling; Heart/physiopathology; Humans; Kaplan-Meier Estimate; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Electron; Mitochondria/metabolism; Mitochondria/ultrastructure; Mitochondrial Diseases/genetics; Mitochondrial Diseases/metabolism; Mutagenesis, Insertional; Myocardium/metabolism; Myocardium/pathology; Myocardium/ultrastructure; NADH Dehydrogenase/genetics; NADH Dehydrogenase/metabolism; RNA Splicing; Reverse Transcriptase Polymerase Chain Reaction

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SODM

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NDUS6

acts_upstream_of_or_within

GO:0022904: respiratory electron transport chain

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4346527

P

Seeded From UniProt

complete

MOUSE:NDUS6

acts_upstream_of_or_within

GO:0006936: muscle contraction

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4346527

P

Seeded From UniProt

complete

MOUSE:NDUS6

acts_upstream_of_or_within

GO:0006631: fatty acid metabolic process

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4346527

P

Seeded From UniProt

complete

MOUSE:NDUS6

acts_upstream_of_or_within

GO:0010259: multicellular organism aging

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4346527

P

Seeded From UniProt

complete

MOUSE:NDUS6

located_in

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NDUS6

acts_upstream_of_or_within

GO:0061458: reproductive system development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4346527

P

Seeded From UniProt

complete

MOUSE:NDUS6

acts_upstream_of_or_within

GO:0072359: circulatory system development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4346527

P

Seeded From UniProt

complete

MOUSE:NDUS6

acts_upstream_of_or_within

GO:0070584: mitochondrion morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4346527

P

Seeded From UniProt

complete

MOUSE:NDUS6

acts_upstream_of_or_within

GO:0035264: multicellular organism growth

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:4346527

P

Seeded From UniProt

complete

MOUSE:SODM

part_of

GO:0005739: mitochondrion

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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