Mitochondrial DNA Maintenance Disorders Lab

Research Activity

Mitochondria are key organelles as they are responsible for supplying the proper form of energy necessary to the cell to exert all its functions. Unlike other cellular organelles, mitochondria possess their own DNA (mtDNA). In humans, the mitochondrial genome is comprised of several copies of a 16 kilobases (kb), double strand DNA (dsDNA) circular molecule. The genes encoded by this small genome are essential for the biosynthesis of the mitochondrial respiratory chain.

The maintenance of mtDNA requires a set of nuclear genes involved in mtDNA replication, in controlling the mitochondrial nucleotide pools, and in mediating mitochondrial fusion and fission. Mutations in these genes are associated with several pathological conditions, hereby referred to as mtDNA maintenance defects (MDMD). Patients with MDMD presents with different phenotypic manifestations, including neuropathy, myopathy, hepatopathy and encephalopathy. The most severe conditions, characterized by depletion of mtDNA (i.e. the reduction of mtDNA copy number in cells), manifest during the neonatal period or early infancy. Although in the majority of the cases the genetic cause triggering the disease is known, the mechanistic process linking the genetic defect to the loss of mtDNA integrity is still poorly understood. Nonetheless, we recently showed that specific DNA secondary structures, called G-quadruplexes (G4s), can form at the mtDNA and interfere with the process of replication leading to mtDNA instability (Doimo et al, 2023).

Our recently established group aims at elucidating the molecular mechanisms regulating the maintenance of the mitochondrial genome and particularly how DNA secondary structures and epigenetic modifications impact these processes.

We are developing novel genomic, proteomic and single molecules methodologies and apply them in cell models and patient’s derived tissues. In addition, we are establishing in vivo models of disease that will allow us to explore therapies that can counteract the mtDNA genomic instability and block the progression of the disease.