Molecular interactions and functional dissection of TMEM65: relevance for mitochondrial diseases

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2022

A mutation in the mitochondrial protein TMEM65 has been identified in a pediatric patient with a complex encephalomyopathy disorder. The molecular pathway implicated is unknown because of the lack of information on the TMEM65 protein function. TMEM65 is localized in mitochondria, crucial cellular organelles whose dysregulation gives rise to cellular dysfunction and the so-called mitochondrial diseases. A unique characteristic of mitochondria is that the genes that codify for the mitochondrial proteins, determining the proper function, are present in two different cellular compartments: the nucleus (99% of genes), and the mitochondria (1%The mitochondrial genome (mtDNA) codifies for few but essential proteins, regulating of this information flow that leads from gene to protein is fundamental for mitochondrial and cellular function. Our preliminary results point to TMEM65 as a regulator in the steps that lead from gene to protein (replication, transcription or translation) inside the mitochondria, a hypothesis that this research project wants to validate by using genetic, molecular biology and microscopy approaches, and by choice of adequate cellular models. Indeed, the use of hiPSCs from a donor will be beneficial in understanding how TMEM65 mutation affects hiPSCs differentiation into neurons, a crucial event that likely explains the early phenotype. We expect the obtained results will identify TMEM65 function and relevance for the diasease.