Functional characterization of the mitochondrial protein CCDC58 and its role in 3-methylglutaconic aciduria type 9

This project has been funded thanks to the Joint Call Fondazione Cariplo and Fondazione Telethon 2023 Mitochondria are intracellular structures that house about 1500 proteins, showing a wide range of functions. Only 13 are synthetized inside these organelles, thereby all the other proteins need to be imported, and this occur through sophisticated import systems. Importantly, alterations in the protein import machinery, due to mutations in one or more genes that regulate this process, lead to the onset and development of several mitochondrial disorders. Among them, 3-Methylglutaconic aciduria (3-MGA-uria) type 9 (MGCA9), a rare invalidating genetic disorder characterized by severe symptoms, is associated with mutations in TIMM50 gene, encoding for a protein that is crucial for the mitochondrial protein import. In this proposal, we shed light on an understudied mitochondrial factor, called CCDC58. We observed high levels of this protein when the import machinery is compromised by inactivation of TIMM50, and the upregulation of CCDC58 triggers drastic mitochondrial defects, which resemble those observed in cells of MGCA9 patients. Moreover, the effects of CCDC58 could be related to the regulation of a mitochondrial channel called mPTP, whose activation is crucial in triggering mitochondrial derangements and cell death. Therefore, with this project we propose a novel mechanism that could be involved in the pathogenesis of MGCA9, based on the link between the unknown protein CCDC58 and mPTP functions. Importantly, the mPTP could targeted by different pharmacological compounds, suggesting potential novel therapeutic strategies for MGCA9 treatment.