Compositions and methods for treatment of mitochondrial respiratory chain dysfunction and other mitochondrial disorders

A reiterative screening method for identifying agents effective to modulate mitochondrial respiratory chain function in at least three evolutionarily distinct biological species selected from C. elegans, D. rerio, and H. sapiens, comprising;

• a) (i) contacting genetically altered C. elegans, said genetic alteration impacting a gene associated with mitochondrial respiratory chain dysfunction, and wild-type C. elegans lacking said genetic alteration with a test agent or
• (ii) contacting genetically altered D. rerio, carrying a cognate genetic alteration from step a)(i) in C. elegans and wild-type D. rerio lacking said genetic alteration with a test agent;
• b) assessing one or more cellular parameters associated with mitochondrial respiratory chain function in C. elegans of step a) (i);
• and identifying said agent as a modulator of said one or more cellular parameters associated with mitochondrial respiratory chain function in C. elegans;
• or
• c) assessing one or more cellular parameters associated with mitochondrial respiratory chain function in D. rerio carrying said genetic alteration relative to wild type D. rerio and identifying said agent as a modulator of said one or more cellular parameters associated with mitochondrial respiratory chain function in said C. elegans, or D. rerio or both C. elegans and D. rerio;
• and
• d) contacting a fibroblast cell, lymphoblastoid cell line, derived iPSC or differentially terminated cell line from H. sapiens carrying a mutation in the cognate human gene with said agent identified as a modulator-of step c), assessing one or more cellular parameters associated with mitochondrial respiratory chain function in said fibroblast, lymphoblastoid cell line, derived iPSC or differentially terminated cell line and identifying said agent as a modulator of one or more cellular parameters associated with respiratory chain function in H. sapiens, and at least one of C. elegans, and D. rerio.