Advanced search

Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease

Grant number: 17/04372-0
Support type:Research Projects - Thematic Grants
Duration: September 01, 2017 - August 31, 2022
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Nadja Cristhina de Souza Pinto
Grantee:
Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo, SP, Brazil
Assoc. researchers:Cláudia Ferreira da Rosa Sobreira ; Marcos Roberto Chiaratti ; Marcos Túlio de Oliveira ; Rodolfo Borges dos Reis

Abstract

Mitochondria are essential organelles in eukaryotic cells as they are involved in central pathways including energy metabolism and intracellular signaling. Besides being the main cellular site for ATP generation, they are involved in redox signaling, intracellular calcium homeostasis and cell fate after stress. Moreover, they contain their own independent genome. In humans, the mitochondrial DNA (mtDNA) is 16,569 base-pair long and encodes for 13 proteins, 2 rRNAs and 22 tRNAs. But despite its small size, its integrity is essential for cellular function, as mutations in the mtDNA cause several human syndromes, from moderate to severe clinical phenotypes. Nonetheless, the mtDNA is particularly susceptible to DNA damage accumulation, as it lies close to the electron transport chain where most cellular reactive oxygen species are generated. In fact, mtDNA accumulates significantly more DNA lesions than nuclear DNA. Thus, a better understanding of the molecular mechanisms involved in maintaining mtDNA stability is essential for comprehending the pathophysiological aspects of diseases. In this context, this project is divided into 5 subprojects, aiming at gaining a comprehensive understanding of the role of mtDNA maintenance in health and disease. These are: 1) characterization of mitochondrial DNA repair; 2) role of replication proteins in mtDNA stability; 3) role of mitochondrial rad51 in female germline and fertility; 4) mtDNA heterogeneity in renal carcinoma; and 5) mtDNA instability in exercise-intolerant patients. The results obtained from these studies will further our understanding of the molecular mechanisms responsible for maintaining mtDNA stability and on how these contribute to pathological processes, thus supporting the development of new therapeutic and preventive approaches. (AU)