Mutations in Assembly Factors Required for the Biogenesis of Mitochondrial Respiratory Chain

The mitochondrial respiratory chain, which provides to the cells most of their ATP requirement, is composed of five multisubunit complexes. Its biogenesis is a multi-step process characterized by the sequential formation of intermediate assemblies composed of subunits encoded by two distinct genomes, mitochondrial or nuclear DNA. This process is assisted by a diverse set of ancillary proteins of nuclear origin called assembly factors that are not part of the final complexes and exert different functions. Mutations in several genes encoding these proteins have been identified in patients affected by mitochondrial diseases, exceeding those found in genes encoding structural subunits for some complexes. The hallmark of these disorders, which are often multisystemic and mainly affect high energy demanding organs, is the broad genetic and clinical heterogeneity, making their diagnosis problematic. The number of assembly factors associated with human diseases is rapidly increasing, owing to the employment of next generation sequencing methods in the diagnostic workflow. Therapy for these conditions is mostly based on supportive care, emphasizing the need to elucidate their pathological mechanisms to find novel treatments.