Mitochondrial myopathy associated to FDX2 mutations: a crossroad of FeS protein biogenesis and Coenzyme Q biosynthesis

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

Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is a rare inherited neuromuscular disorder, clinically characterized by childhood onset of progressive muscle weakness and exercise intolerance. Further, more variable features of this disorder may include optic atrophy, reversible or partially reversible leukoencephalopathy, and later onset of a sensory-motor polyneuropathy. This disease has recently emerged: it has been firstly identified in 2014 in a 15-year-old girl and up to now two pathogenic mutations were found in eight individuals. MEOAL is caused by mutations of ferredoxin-2 (FDX2), a protein which appears central for energy production by mitochondria, the “cells’ power plants”. Indeed, FDX2 has been claimed to participate in the formation of iron-sulfur clusters, which are essential cofactors for proper mitochondrial function, and some hints suggest that it could be also involved in the biosynthesis of Coenzyme Q, a molecule which plays a key role in several biological processes, human diseases and therapeutic regimens. However, to date several gaps remain in the complete understanding of the role of FDX2 in mitochondrial pathophysiology and there is currently no specific cure or effective treatment for MEOAL patients. In this proposal we aim at clarifying how FDX2 works in healthy cells and how known pathogenic mutations impair its functions. Defining the molecular features of the disease is a crucial task that will undoubtedly facilitate the development of novel therapeutic strategies for MEOAL disease.