The Role of ECSIT in Mitochondrial Dysfunction Mediated Cardiomyopathy

Nicol, Thomas Leslie (2018). The Role of ECSIT in Mitochondrial Dysfunction Mediated Cardiomyopathy. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000da74

Abstract

The evolutionarily conserved signalling intermediate in the toll pathway (ECSIT) is a 50 kDa protein involved in the function of many pathways and implicated in a variety of phenotypes. It functions as part of the toll pathway by integrating the signal from several toll receptors and facilitating the activation of downstream proteins NFКB, JNK and P38 MAPK. It functions as part of the bone morphogenetic protein pathway through interaction with SMAD4 allowing for normal embryonic development. It also functions as a mitochondrial complex I assembly factor and loss of function leads to a reduction in fully assembled complex I.

As part of a large scale ENU mutagenesis screen, The Harwell Ageing Screen, a novel missense mutation (N209I) was identified in ECSIT which resulted in a hypertrophic cardiomyopathy phenotype in homozygous mutant animals.

Further investigation revealed this phenotype to be a result of a loss of function in ECSIT’s role as a complex I assembly factor. Mitochondria from EcsitN209I/N209I hearts showed a reduction in total complex I protein as well as a loss of enzymatic activity and fully assembled complex I. Interestingly, this mitochondrial dysfunction was limited to the heart with other tissues maintaining protein levels and complex I function at or close to wild type levels, suggesting that there may be tissue specific differences in the complex I assembly pathway. Investigation of the assembly pathway using first and second dimensional blue native PAGE suggests that this tissue specific pathway may involve the formation of a previously undescribed fragment of ECSIT that is present in heart tissue but absent from other tissues tested, is associated with fully assembled complex I in wild type mitochondria but absent in EcsitN209I/N209I hearts.

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