Abstract
Mn superoxide dismutase (MnSOD)-deficient mice (Sod2−/−) suffer from mitochondrial damage and have various survival times and phenotypic presentations that are dependent on the genetic background of the mutant mice. The mitochondrial NADPH transhydrogenase (NNT) was identified as a putative genetic modifier based on a genome-wide quantitative trait association study on the molecular defect of the protein in more severely affected Sod2−/− mice and on the biological function of NNT. Hence, Sod2−/− mice on the C57BL/6J (B6J) background have the shortest survival time, and the mice are homozygous for the truncated Nnt allele (Nnt T). On the other hand, genetic backgrounds that support longer survival of Sod2−/− mice all have at least one normal copy of Nnt (Nnt W). To confirm the role of NNT in the phenotypic modification of Sod2−/− mice, we introduced a normal copy of Nnt allele from a C57BL/6 substrain into B6J-Sod2−/− mice and analyzed survival time, cardiac functions, and histopathology of the heart. The study results show that the presence of a normal Nnt allele preserves cardiac function, delays the onset of heart failure, and extends the survival of B6J-Sod2−/− mice to the end of gestation. Postnatal survival, however, is not supported. Consequently, the majority of B6J-Sod2−/− mice died within a few hours after birth and only a few survived for 5–6 days. The study results suggest that NNT is important for normal development and function of fetal hearts and that there may be other genetic modifier(s) important for postnatal survival of Sod2−/− mice.
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Acknowledgments
We thank Xinli Wang for excellent animal care and Tim Doyle at the Stanford Center for Innovation in In-Vivo Imaging for instructing us on the in vivo microimaging procedure. This work was supported by funding from the National Institutes of Health (AG24400) and from the Stanford Digestive Disease Center, and by the resources and facilities at the VA Palo Alto Health Care System.
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Kim, A., Chen, CH., Ursell, P. et al. Genetic modifier of mitochondrial superoxide dismutase-deficient mice delays heart failure and prolongs survival. Mamm Genome 21, 534–542 (2010). https://doi.org/10.1007/s00335-010-9299-x
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DOI: https://doi.org/10.1007/s00335-010-9299-x