RICERCA ITALIANA     

Variability and function of mitochondrial mutations in physiological and pathological conditions

Università degli Studi di Bologna

Abstract

Recent years have witnessed considerable progress in understanding basic mitochondrial genetics and the relationship between mutations and disease phenotypes. Although our present knowledge indicates that mitochondrial DNA (mtDNA) mutations are an important cause of disease, the true impact of these mutations on human health is still to be determined.
Mitochondria are the main producers of cellular ATP by oxidative phosphorylation and the only location of extra-chromosomal DNA within the mammalian cell. In recent years many studies have been performed to assess whether mitochondria are involved in cancer, given that rapidly growing cancer cells exhibit a higher rate of glycolysis and reduce pyruvate oxidation.
Several mtDNA variants have been associated to different tumor types, but in most cases no evidence is available on the relevance of these mtDNA mutations for the biochemical phenotype.
Recently, in a cell model of thyroid oncocytoma, a tumor characterized by cells with an abnormal mitochondrial proliferation, we have identified two pathogenic mutations in the mtDNA, leading to a severe mitochondrial energetic dysfunction. These results together with other data reported in literature suggest a role of mtDNA mutations in tumor development. We are now focused in detecting and functionally characterizing mutations in the mtDNA of different tumors.
We are interested in creating a computational system to catalog and predict the potential damaging >>>

Principal Investigator

Giovanni Romeo Università degli Studi di BOLOGNA

Research Objectives

The mitochondrial genome consists of a multicopy, circular dsDNA molecule (16.6kb in humans), which encodes 13 polypeptides of the oxidative phosphorylation system and the necessary RNA machinery for translation within the organelle. The polyploid nature of the mitochondrial DNA (mtDNA) gives rise to an important feature of mitochondrial genetics, homoplasmy and heteroplasmy. Homoplasmy is a situation where all copies of the mitochondrial genome are identical, whereas coexistence of both wild-type and mutant mtDNA is defined as heteroplasmy. In the presence of heteroplasmy, a threshold level of mutation has to be achieved to cause the biochemical defect and the clinical expression of the disease.
Human populations can be divided into several mtDNA haplogroups based on specific single nucleotide polymorphisms (SNPs), reflecting mutations accumulated by a well identified lineage. Haplogroup association studies have been used to define the role of mtDNA mutations in complex diseases.
Owing to the crucial role of mitochondria in both cell life and death, in recent years many studies have been performed to assess whether these organelles are involved in cancer.
Although a variety of mtDNA mutations has been associated with different types of cancer, in most cases no evidence was provided on the relevance of these mtDNA mutations with regard to the biochemical phenotype.
Recently, in a cell model of thyroid oncocytoma, a tumor characterized by cells >>>

Timescale

24 months

National and international background

Recent years have witnessed considerable progress in understanding basic mitochondrial genetics and the relationship between inherited mutations and disease phenotypes, and in identifying acquired mtDNA mutations in both ageing and cancer (for a review see [1]).
The mtDNA is also central to the study of evolutionary genetics, and has an important role in forensic medicine.
The mammalian mitochondrial genome consists of a multicopy, circular dsDNA molecule (16.6kb in humans), which encodes 13 polypeptides of the oxidative phosphorylation system and the necessary RNA machinery (2 rRNAs and 22 tRNAs) for their translation within the organelle. The remaining protein subunits are nuclear-encoded, and are specifically targeted to their correct location within the organelle. Within a genome size of about 16 Kb, almost all the organisms have the same genetic content, with a few small exceptions, but the genetic information is differently distributed in the various metazoan lineages, except for vertebrates in which gene organization is extremely well conserved over a time-span of less than 350 My. In addition, because the selection effect is more or less evident according to the geographic origin of the genomes, climatic adaptation may be inferred as one of the major forces in primate mtDNA evolution.
The polyploid nature of the mitochondrial genome gives rise to an important feature of mitochondrial genetics, homoplasmy and heteroplasmy. Homoplasmy is when all >>>