Title: Scientific research in the area of mitochondrial medicine
Funder: Medical Research Foundation

Abstract: Pearson marrow pancreas syndrome (PMPS) is a sporadic mitochondrial disease, resulting from the clonal expansion of a mutated mitochondrial DNA (mtDNA) molecule bearing a large-scale deletion, and therefore missing essential genetic information. This event occurs sporadically, in either the maternal oocyte or early during the development of the embryo. As the large scale deletion invariably contains tRNA genes, in addition to genes encoding subunits of the mtDNA-dependent respiratory chain complexes (CI, III, IV and V), the mutant mtDNA is translationally incompetent, and relies on the presence of a variable percentage of wild-type mtDNA that partly complements the missing genes of the deleted mtDNA species. This condition is termed heteroplasmy PMPS is characterized by the presence of a substantial amount of deleted mtDNA in virtually all tissue of the affected individual, including the haemopoietic system, the gastroenteric system, including the exocrine pancreas, and the post-mitotic, highly specialized tissues, e.g. brain, skeletal muscle, and heart. Because of the diffuse, multiorgan distribution of mtDNA, the initial symptoms are characterized by the failure of the haemopoietic tissue, where cells accumulate high levels of heteroplasmy, leading to severe sideroblastic anaemia, neutropenia, and thromobocytopenia. The exocrine pancreas is also often affected, causing frequent diarrhea and intestinal pain, and growth retardation due to malabsorption. Other organs can also be initially affected in PMPS, such as liver, kidneys, heart, eyes, ears, and/or brain. Unfortunately, mtDNA is refractory to the standard manipulation developed to modify nuclear DNA and bacterial DNA. Nevertheless, the presence of a substantial amount of wild-type mtDNA in affected tissues may in principle be exploited to reduce the mutated heteroplasmic load below the critical threshold that determines the bioenergetics failure and disease. The controlled manipulation of heteroplasmy can be achieved by using mitochondrially-directed zinc-finger endonucleases or mitochondrially directed TALENS, specific for the mutant mtDNA species, either mtDNA or mtDNA carrying specific, pathogenic point mutations. A second possible approach is to promote the destruction of mutant, energetically spent mitochondria, by improving the mechanisms devoted to carry out mitochondrial-specific autophagy (mitophagy). A third approach consists in promoting mitochondrial biogenesis, in order to increase the amount of efficient mitochondrial respiratory unit and overcome the deleterious effects of mtDNA at the phenotype level.We propose here (i) to develop reliable cell, organoid and mouse models for PMPS, which will allow us in order (ii) to test new therapeutic approaches aimed at reducing the burden of mutated mtDNA. Recent technological advances should enable us to introduce targeted manipulations in mtDNA, and reduce the mutant heteroplasmic load below the threshold critical for clinical manifestation of the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CONGENITAL DISORDERS