An X-chromosome linked mouse model (Ndufa1S55A ) for systemic partial Complex I deficiency for studying predisposition to neurodegeneration and other diseases

Neurochemistry International
Chul KimNagendra Yadava

Abstract

The respiratory chain Complex I deficiencies are the most common cause of mitochondrial diseases. Complex I biogenesis is controlled by 58 genes and at least 47 of these cause mitochondrial disease in humans. Two of these are X-chromosome linked nuclear (nDNA) genes (NDUFA1 and NDUFB11), and 7 are mitochondrial (mtDNA, MT-ND1-6, -4L) genes, which may be responsible for sex-dependent variation in the presentation of mitochondrial diseases. In this study, we describe an X-chromosome linked mouse model (Ndufa1S55A) for systemic partial Complex I deficiency. By homologous recombination, a point mutation T > G within 55th codon of the Ndufa1 gene was introduced. The resulting allele Ndufa1S55A introduced systemic serine-55-alanine (S55A) mutation within the MWFE protein, which is essential for Complex I assembly and stability. The S55A mutation caused systemic partial Complex I deficiency of ∼50% in both sexes. The mutant males (Ndufa1S55A/Y) displayed reduced respiratory exchange ratio (RER) and produced less body heat. They were also hypoactive and ate less. They showed age-dependent Purkinje neurons degeneration. Metabolic profiling of brain, liver and serum from males showed reduced heme levels in mutants, which correlated with ...Continue Reading

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Dec 29, 2020·Biochimica Et Biophysica Acta. General Subjects·Kaori Ishikawa, Kazuto Nakada

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