Defects in the primary metabolic functions of mitochondria, the cell’s‘power-plants’, underlie a diverse range of human pathologies, includingrare neuromuscular syndromes, many cases of common multifactorialdiseases (e.g epilepsy, deafness, diabetes), neurodegenerativeconditions such as Parkinson’s disease (PD), and devastating metabolicdisorders of infancy. Mitochondrial dysfunction is also a major cause oftissue damage in heart attack and stroke, and is involved incancer progression. This project will facilitate an R&D effort todevelop a common genetic therapy for this vast range of diseases, takingadvantage of the fact that lower organisms possess a built-inbiochemical mechanism for relieving the stress caused by mitochondrialdysfunction, using alternative respiratory chain enzymes that simplyby-pass the problem. Under ERC Project 232738 (MITO BY-PASS) we havesucceeded in expressing the alternative oxidase AOX from the seasquirt Ciona intestinalis in mammalian cells and transgenic flies. Inthe fruit-fly, AOX expression overcomes the lethality of poisonsdirected at mitochondria, and cures flies of genetic defects thatproduce features equivalent to PD or fatal mitochondrial diseases ofinfancy. Preliminary data on mammalian models also indicates that thegene can be safely expressed, and contributes similar benefits. Thesenow constitute a key validation tool to test the potential for AOXtherapy of many human diseases. This PoC project will undertake thecrucial next steps in the development of AOX therapy by implementing apartner search and negotiating terms for testing the technology in manydifferent mammalian models of common diseases associated withmitochondrial dysfunction, and by soliciting major investment forthe development of AOX therapy from both public and private-sector partners.