Research Topic

Impact of nuclear genetic variants on mitochondrial pathophysiology

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The advent of next-generation sequencing (NGS) allowed the identifications of a considerable number of novel genetic variants and the determination of precise frequency of common genetic polymorphisms in human population. Thanks to the whole exome sequencing (WES), it is estimated the mutations causing ...

The advent of next-generation sequencing (NGS) allowed the identifications of a considerable number of novel genetic variants and the determination of precise frequency of common genetic polymorphisms in human population. Thanks to the whole exome sequencing (WES), it is estimated the mutations causing monogenic diseases could be identified in about 85% of cases. This un-biased approach is extremely useful for disorders lacking consistent genotype-phenotype correlation. While NGS makes genetic analyses much faster, it leads to enormous amounts of sequencing data and requires interpretation and validation of identified novel variants. Bioinformatic analyses and functional studies have become extremely important, often necessary, steps in NGS studies. At this regard, model organisms, like yeast, C. elegans, D. melanogaster, zebrafish and mouse, offer a unique opportunity for understanding molecular basis of human pathogenesis through in vivo studies. Among diseases whose molecular genetics has been improved thanks to WES in the last three years there are mitochondria disorders, a heterogeneous group of syndromes characterized by primary or secondary defects in the mitochondrial oxidative phosphorylation (OXPHOS) system. In addition to mutations in mitochondrial DNA (mtDNA), several mutations responsible for mitochondrial disorders have been reported in nuclear genes affecting different mitochondrial functions: mitochondrial respiratory chain biogenesis, mtDNA replication and translation, mito-dynamics, Fe-S cluster assembly, reactive oxidative species (ROS) production, calcium homeostasis and apoptosis. Moreover mitochondrial dysfunctions, including accumulation of mtDNA mutations, deletions and depletion, have been associated with cancer, neurodegenerative disorders and aging.

The aim of this Research Topic is to clarify the effects of nuclear common or uncommon genetic variants, identified through classical Sanger sequencing or NGS, on mitochondrial physiology and pathology. At this regard, subjects of interest include but are not limited to:
- identification and characterization of nuclear genetic variants causing mitochondrial dysfunction
- study of the correlation or association between nuclear genetic polymorphisms and mitochondrial functionality, including mutations which affect aging, mtDNA mutability and stability, ROS production, and apoptosis
- reports of haplotypes which are associated to altered (decreased or increased) OXPHOS activity
- biochemical analysis of mutated nuclear-encoded mitochondrial enzymes
- pharmacogenetics studies of how nuclear allelic variants influence the response to drugs which have direct or indirect effects on mitochondrial physiology
- use of model systems to study the molecular effects on mitochondria of human genetics variants and to clarify the role of nuclear genes in mitochondrial diseases
- use of bioinformatic tools to predict the pathogenicity of mutations in nuclear-encoded mitochondrial proteins
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