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Induced pluripotent stem cells derived from patients with mitochondrial diseases as a model for studying mitochondrial inheritance

Grant number: 13/13869-5
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): September 01, 2013
Effective date (End): August 31, 2015
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Marcos Roberto Chiaratti
Grantee:Carolina Habermann Macabelli
Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
Associated research grant:12/50231-6 - Molecular basis of mitochondrial inheritance: the role of mitochondrial fusion, AP.JP

Abstract

Mitochondrial dysfunctions caused by mutations in the mitochondrial DNA (mtDNA) represent an important group of human pathologies. However, it is not possible to predict with accuracy the risk of a woman with mutant mtDNA to transmit her pathology to her descendants. This is mainly due to out limited understanding of the molecular basis of mitochondrial inheritance. Since development of a technology that enabled derivation of induced pluripotent stem cells (iPSCs) from in vitro culture of somatic cells, iPSCs have become an interesting model to study mitochondrial inheritance. Like embryonic stem cells (ESCs), the nuclear reprogramming induced to derive iPSCs results in alterations in mitochondria associated to undeveloped cristae, low mitochondrial activity and reduced amount of mitochondria and mtDNAs per cell. Derivation of iPSCs from patients with pathogenic mtDNA mutations has revealed that the mutant load decreases through in vitro culture of iPSCs, resulting in elimination of mutant mtDNA. In agreement with previous in vivo studies with humans and mice, these results suggest the existence of a specific mechanism that eliminates mutant mtDNA in germ line. Thus, the aim of this work is to use iPSCs derived from patients with mitochondrial disorders to investigate the existence of a mechanism eliminates mtDNA molecules with pathogenic mutations. In this way, it will be used heteroplasmic fibroblasts harboring a point mutation A3243G in mtDNA causing mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS); heteroplasmic fibroblasts harboring a deletion in mtDNA causing Kearn-Sayre Syndrome (KSS); and, homoplasmic fibroblasts harboring wild-type mtDNAs. These three lineages will be used for derivation of iPSCs and comparison of mtDNA copy number and mutant load through in vitro culture of iPSCs. In the case of we find a decrease of mutant load in iPSCs through culture, we will investigate if there is an involvement of an autophagic mechanism in elimination of mitochondria with mutant mtDNA. In this case, the iPSC lineage showing such decrease in mutant load will be treated with a promoter (rapamicine) or an inhibitor (mdivi-1) of autophagy and both groups will be compared with an untreated control regarding mtDNA copy number and mutant load. It is expected from this work to expand our knowledge on the mechanisms involved in mitochondrial inheritance, especially when regarding mtDNA mutations. The use of iPSCs to study mitochondrial inheritance seems to be an interesting alternative as availability of biological material (e.g., oocytes, embryos and ESCs) from patients with mitochondrial disorders is scarce and there is no animal model for mitochondrial diseases.

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Scientific publications
(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)
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)

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