Mitochondria are cool

Research

Mitochondria and energy metabolism in cell fate conversion and neural commitment

Our current projects focus on two neurological genetic disorders affecting basal ganglia: Leigh syndrome (LS) and Huntington’s disease (HD).
In LS, the mitochondrial dysfunction is primary, since the disease is caused by mutations in genes encoding for proteins of the mitochondrial oxidative phosphorylation (OXPHOS). In HD, instead, the mitochondrial implication is only secondary in the pathogenesis and may be due to a pathological interaction of the mutated Huntingtin protein with mitochondria. By studying these two diseases, we are currently attempting to address the role of mitochondrial dysfunction in neural impairment. Using patient iPSCs, we wish to develop innovative drug discovery approaches.

 

Leigh syndrome

Leigh syndrome (LS) is the most severe pediatric mitochondrial disorder. Mitochondrial disorders are incurable diseases caused by mutations in genes encoding for components of the mitochondrial oxidative phosphorylation (OXPHOS) machinery. The mutations can occur in the nuclear DNA (nDNA) or in the mitochondrial DNA (mtDNA). LS is a progressive encephalopathy characterized by loss of controlled movement and psychomotor regression. LS particularly affect neurons in the basal ganglia, which are brain structures that are highly dependent on mitochondrial-based energy production. One of the major hurdle for the development of therapies for mitochondrial disorders is the paucity of model systems.

Our hypothesis is that by generating several iPSC lines carrying distinct LS-causing mutations, we may be able to unveil common pathogenetic mechanisms at the bases of the neural pathology characteristic of the disease.

 

Team members working on this project:

Current:

Alumni:

 

Huntington’s disease

Huntington’s disease (HD) is an untreatable neurodegenerative disorder caused by an abnormal expansion of a CAG repeat in the gene encoding for the protein Huntingtin (HTT). HD is characterized by neuronal loss in several brain regions and particularly in the striatum. Therefore, although mutant HTT is present in every cell of the body, neuronal cells may be particularly sensitive to its toxicity. One potential reason underlying the specific neuronal death is that neurons are highly dependent on mitochondrial function, which is impaired in HD.

Our hypothesis is that measures that could prevent the occurrence of mitochondrial impairment in HD neurons may represent promising interventional strategies for HD.

To address this hypothesis, we generate genetically corrected HD iPSC lines using CRISPR/Cas9 genome editing.

 

Team members working on this project:

Current:

Alumni:

 

A proof-of-principle application of our iPSC-based drug discovery approach was carried out for MT-ATP6 mutations (Lorenz et al, Cell Stem Cell, 2017). There, by using libraries of FDA-approved compounds, we were able to identify a class of compounds that we found able to normalize the calcium dyshomeostasis detected in patient neural progenitor cells (NPCs) and post-mitotic neurons. The fact that these drugs are already considered by the FDA to be safe for clinical usage may allow their quick repositioning and the rapid translation of our findings into medical applications.

(A). NPCs are homogeneous and generate neurons and glia cells. (B) Patient-derived NPCs carrying a mutation in the mtDNA gene MT-ATP6 exhibit defects in the mitochondrial membrane potential (MMP) and calcium homeostasis that were not present in other cell types (B-D). We used the MMP phenotype to carry out a proof-of-concept compound screening that identified the PDE5 inhibitor avanafil that we confirmed to be able to ameliorate the calcium defects in patient NPCs and patient neurons.