The present disclosure provides transgenic nematode systems for assessing function of heterologous genes, their variants and drug discovery. The transgenic nematodes contain a heterologous gene that is inserted via homologous recombination at the native locus replacing and removing the nematode ortholog, wherein expression of the heterologous gene rescues function of the removed nematode ortholog and a transgenic control animal is provided. The heterologous gene may be further modified to provide a variant, such as a human clinical variant, whereby a transgenic test animal is provided. Those transgenic test animals are used in methods to assess function of the heterologous variant and drug screens to find therapeutic candidates reversing deviant activity back to wildtype.

Compositions and methods for modulation by upregulation (up modulation) and/or downregulation (down modulation) of mitophagy are described for the treatment of mitochondrial disorders including OPA-1 related disease and Single Large Scale Mitochondrial DNA Deletion (SLSMD). Also disclosed are a number of screening assays and gene targets having utility for the identification of agents which modulate the phenotype associated with such disorders.

Compositions and methods for modulation by upregulation (up modulation) and/or downregulation (down modulation) of mitophagy are described for the treatment of mitochondrial disorders including OPA-1 related disease and Single Large Scale Mitochondrial DNA Deletion (SLSMD). Also disclosed are a number of screening assays and gene targets having utility for the identification of agents which modulate the phenotype associated with such disorders.