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

Grant number: 17/04372-0
Support Opportunities:Research Projects - Thematic Grants
Duration: September 01, 2017 - August 31, 2023
Field of knowledge:Biological Sciences - Genetics - Mutagenesis
Principal Investigator:Nadja Cristhina de Souza Pinto
Grantee:Nadja Cristhina de Souza Pinto
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Pesquisadores principais:
Cláudia Ferreira da Rosa Sobreira ; Marcos Túlio de Oliveira ; Rodolfo Borges dos Reis
Associated researchers:Cláudia Ferreira da Rosa Sobreira ; Marcos Roberto Chiaratti ; Marcos Túlio de Oliveira ; Rodolfo Borges dos Reis
Associated grant(s):17/25916-9 - Mitochondrial dysfunctions and DNA damage in oocytes: implications to fertility, AV.EXT
17/22168-1 - Multi-user equipment approved in grant 2017/04372-0, equipment Digital Droplet PCR System and accessories, AP.EMU
Associated scholarship(s):22/02482-1 - Mitochondrial DNA Methylation Impacts The P53/Pgc1-alpha/Nrf1 Axis in a Redox Imbalance Context, BP.DD
22/01155-7 - Study of mitochondrial H2O2 mediated redox signaling in XPC deficient models, BP.PD
22/11964-0 - Maternal inheritance of mitochondrial and endoplasmic reticulum abnormalities, BP.IC
+ associated scholarships 22/09281-1 - Analysis of mutation rate in offspring born to mice with oocyte-specific deficiency of Rad51, BP.IC
21/11123-2 - Study of mitochondrial mutagenesis induced by hydrogen peroxide and methyl-methanesulfonate in mouse fibroblasts, BP.MS
22/03395-5 - Mitochondrial oxygen consumption in the central nervous system and in the musculature of Twinkle mutant Drosophila lines, BP.IC
21/04835-6 - Role of mitochondria-endoplasmic reticulum interaction on maternal inheritance of metabolic syndromes, BP.IC
21/05116-3 - Role of TFAM in modulation of DNA pol gamma activity by p53, BP.PD
18/26555-2 - Study of role of DNA polymerase eta in cellular responses and carcinogenesis induced by ultraviolet light A, BP.PD
18/24977-7 - Analysis of mitochondrial genome heterogeneity in clear cell renal carcinoma., BP.PD
18/23744-9 - Investigation of the role of Alkyladenine DNA glycosylase (AAG) in the repair of alkylated bases in the mitochondrial DNA of mice, BP.MS
19/00480-9 - TT-3 Technical training scholarship, mitochondrial genetics Laboratory Dedication: 20 hours per week, 24 months, BP.TT
18/20028-0 - Does autophagic deficiency increases accumulation of NZB Mitochondrial DNA in the liver?, BP.IC
18/07700-1 - Role of TFAM in modulation of DNA pol gamma activity by p53, BP.PD
18/06119-3 - Mfn1 knockout in oocytes arrests folliculogenesis in mice through inhibiting the PI3K-Akt pathway, BP.IC
18/04471-1 - Mitochondrial localization of MRN complex components in mammal cells, BP.IC
18/04443-8 - The role of mitochondrial transcription factor an in protecting DNA from oxidative damage, BP.DD - associated scholarships


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)

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Scientific publications (14)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MORI, MATEUS PRATES; DE SOUZA-PINTO, NADJA CRISTHINA. Role of mitochondrial dysfunction in the pathophysiology of DNA repair disorders. Cell Biology International, v. 42, n. 6, SI, p. 643-650, . (17/04372-0, 16/15407-7)
MORI, MATEUS PRATES; DE SOUZA-PINTO, NADJA CRISTHINA. PPRC1, but not PGC-1 alpha, levels directly correlate with expression of mitochondrial proteins in human dermal fibroblasts. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, . (16/15407-7, 17/04372-0, 10/51906-1)
MACHADO, THIAGO S.; MACABELLI, CAROLINA H.; DEL COLLADO, MAITE; MEIRELLES, V, FLAVIO; GUIMARAES, FRANCISCO E. G.; CHIARATTI, MARCOS R.. Evidence of Selection Against Damaged Mitochondria During Early Embryogenesis in the Mouse. FRONTIERS IN GENETICS, v. 11, . (12/50231-6, 13/13869-5, 09/54035-4, 12/12951-7, 17/05899-2, 17/04372-0)
FREIRE, T. S.; MORI, M. P.; MIRANDA, J. N. F. A.; MUTA, L. Y. M.; MACHADO, F. T.; MORENO, N. C.; SOUZA-PINTO, N. C.. Increased H2O2 levels and p53 stabilization lead to mitochondrial dysfunction in XPC-deficient cells. Carcinogenesis, v. 42, n. 11, p. 1380-1389, . (17/04372-0, 18/04471-1, 10/51906-1, 18/26555-2, 19/00480-9, 16/15407-7)
GARCIA, BRUNA M.; MACHADO, THIAGO S.; CARVALHO, KAREN F.; NOLASCO, PATRICIA; NOCITI, RICARDO P.; DEL COLLADO, MAITE; CAPO BIANCO, MARIA J. D.; GREJO, MATEUS P.; AUGUSTO NETO, JOSE DJACI; SUGIYAMA, FABRICIA H. C.; et al. Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis. MOLECULAR HUMAN REPRODUCTION, v. 26, n. 12, p. 938-952, . (10/51906-1, 17/05899-2, 17/04372-0, 18/20028-0, 18/06119-3, 16/11935-9, 09/54035-4, 12/50231-6, 16/11942-5)
OLIVEIRA, MARCOS T.; PONTES, CAROLINA DE BOVI; CIESIELSKI, GRZEGORZ L.. Roles of the mitochondrial replisome in mitochondrial DNA deletion formation. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, 1, . (17/04372-0, 14/02253-6)
ERTUZUN, TUGCE; SEMERCI, ASLI; CAKIR, MEHMET EMIN; EKMEKCIOGLU, AYSEGUL; GOK, MEHMET OGUZ; SOLTYS, DANIELA T.; DE SOUZA-PINTO, NADJA C.; SEZERMAN, UGUR; MUFTUOGLU, MELTEM. Investigation of base excision repair gene variants in late-onset Alzheimer's disease. PLoS One, v. 14, n. 8, . (17/04372-0, 10/51906-1)
ZUCCOLOTTO-DOS-REIS, FELIPPE HENRIQUE; ANDRIAO ESCARSO, SILVIA HELENA; ARAUJO, JACKELINE SOUZA; ESPREAFICO, ENILZA MARIA; ALBERICI, LUCIANE CARLA; DA ROSA SOBREIRA, CLAUDIA FERREIRA. Acetyl-CoA-driven respiration in frozen muscle contributes to the diagnosis of mitochondrial disease. EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, v. 51, n. 9, . (17/04372-0, 16/23509-4, 16/10862-8)
MATEUS PRATES MORI; NADJA CRISTHINA DE SOUZA-PINTO. PPRC1, but not PGC-1α, levels directly correlate with expression of mitochondrial proteins in human dermal fibroblasts. GENETICS AND MOLECULAR BIOLOGY, v. 43, n. 1, . (17/04372-0, 16/15407-7, 10/51906-1)
ABRANTES, ALINE B. DE P.; DIAS, GUSTAVO C.; SOUZA-PINTO, NADJA C.; BAPTISTA, MAURICIO S.. p53-Dependent and p53-Independent Responses of Cells Challenged by Photosensitization. Photochemistry and Photobiology, v. 95, n. 1, p. 355-363, . (14/18123-4, 10/51906-1, 17/04372-0, 12/50680-5, 13/07937-8)
ZHANG, HAIXIN; ESPOSITO, MARCO; PEZET, MIKAEL G.; ARYAMAN, JUVID; WEI, WEI; KLIMM, FLORIAN; CALABRESE, CLAUDIA; BURR, STEPHEN P.; MACABELLI, CAROLINA H.; VISCOMI, CARLO; et al. Mitochondrial DNA heteroplasmy is modulated during oocyte development propagating mutation transmission. SCIENCE ADVANCES, v. 7, n. 50, . (17/04372-0, 16/07868-4)
CARVALHO, KAREN F.; MACHADO, THIAGO S.; GARCIA, BRUNA M.; ZANGIROLAMO, AMANDA F.; MACABELLI, CAROLINA H.; SUGIYAMA, FABRICIA H. C.; GREJO, MATEUS P.; NETO, J. DJACI AUGUSTO; TOSTES, KATIANE; RIBEIRO, FERNANDA K. S.; et al. Mitofusin 1 is required for oocyte growth and communication with follicular somatic cells. FASEB JOURNAL, v. 34, n. 6, . (12/50231-6, 16/11935-9, 09/54035-4, 13/08135-2, 17/04372-0, 16/11942-5, 16/07868-4)
BATALHA, CAIO M. P. F.; VERCESI, ANIBAL EUGENIO; SOUZA-PINTO, NADJA C.. The Many Roles Mitochondria Play in Mammalian Aging. Antioxidants & Redox Signaling, . (17/04372-0, 17/17728-8)
GARCIA, GEOVANA S.; OTHONICAR, MURILO F.; OLIVEIRA, MARCOS T.; COUTO-LIMA, CARLOS A.. An Affordable and Efficient ``Homemade{''} Platform for Drosophila Behavioral Studies, and an Accompanying Protocol for Larval Mitochondrial Respirometry. JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, n. 175, . (14/02253-6, 17/04372-0)

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