Deorphanizing and functionalizing the mitochondrial protein TMEM65

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2021

A genetic mutation dramatically reducing the level of the protein TMEM65 has been reported in one patient affected by severe abnormalities of skeletal muscle and brain. Unfortunately, the function of this protein is largely unknown. According to some works, TMEM65 is located in the inner mitochondrial membrane. According to others, it is part of junctions bringing together cardiac cells. A role as transcription factor or protein kinase/phosphatase has been proposed as well. Based on all these contrasting indications, it is clear that TMEM65 has to be considered an “orphan” protein.

 The aim of the project is the functionalization of TMEM65. We indeed recently obtained new and clear preliminary results that convincingly demonstrate that this protein profoundly affects mitochondrial functions. We intend to combine a variety of approaches, including the generation of patient-derived cells and Drosophila melanogaster models to comprehensively study the function of the protein. The project we propose will frame a new hypothesis on disease pathogenesis, linking mitochondrial homeostasis to the neuronal and muscular dysfunction observed in patients.

 Assigning a clear biochemical function to the orphan protein TMEM65 will bring a breakthrough in the understanding of pathogenesis of a rare disease, setting the basis for the design of a therapeutic hypothesis. Despite only a single case of TMEM65-dependent myopathy has been reported so far, other patients carrying mutation in this gene are likely to exist and will be identified in the next future. Interestingly, TMEM65 level has been recently found downregulated in Barth syndrome, a rare X-linked genetic disorder similarly characterized by defects in muscles. This further underlines the urgent need of an authentic understanding of the pathological consequences caused by loss of TMEM65, that are possibly shared among different rare disorders.