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Metabolomics, lipidomics and mitochondrial biogenesis studies in neural progenitor cells derived from patients' fibroblasts with coenzyme Q10 deficiency.

Abstract

Over the last years, CoQ10 deficiencies have been unveiled and the clinical symptoms as well as the molecular mechanisms of the disease have been better understood. CoQ10 is a mobile lipophilic electron carrier localized in the inner mitochondrial membrane and has a critical role in the electron transfer from complex I and II to complex III in electron respiratory chain. In the primary form of the disease involve mutations in genes directly involved in the complex biosynthetic pathway of CoQ10. In the secondary form mutations are in genes indirectly involved in CoQ metabolism. Cerebellar ataxia is the most common symptom of these patients but they can also present encephalomyopathy with recurrent myoglobinuria, severe infantile multisystemic form, isolated myopathy, nephrotic syndrome and Leigh syndrome. Since CoQ10 disease exhibits a treatable condition is clearly important the early supplementation of oral CoQ10. Nevertheless, it is known that due to CoQ10 lipophilic properties only a small fraction reaches the plasma. At present, new strategies have been discussed to improve the bioviability of CoQ10 by reactivating its endogenous syntheses using chemical agent that elevates mitochondrial biogenesis. Neurological impairment is commonly found in most. In the present project we propose to study the mechanisms underlying the CoQ10 deficient using patient's fibroblasts with CoQ10 deficient reprogramming them into induced Pluripotent Stem cells (iPSc) and consequent differentiation into neural progenitor cells (NPc) and neurons. We plan to study the effects of CoQ10 deficiency on metabolism, evaluate the metabolites and lipids, cellular redox state, and study the mitochondrial biogenesis enhancement as a form to increase ATP production. This project will contribute to the better understanding of the pathophysiology of these diseases. (AU)

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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)
ARITA, JULIANA HARUMI; BARROS, MARIO H.; RAVAGNANI, FELIPE GUSTAVO; ZIOSI, MARCELLO; SANCHES, LIVIA RENTAS; PICOSSE, FABIOLA ROSA; LOPES, TANIA OLIVEIRA; AGUIAR, PATRICIA DE CARVALHO; MACABELLI, CAROLINA HABERMANN; CHIARATTI, MARCOS R.; et al. Metabolic studies of a patient harbouring a novel S487L mutation in the catalytic subunit of AMPK. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1864, n. 5, A, p. 1896-1903, . (15/23549-3, 13/07937-8, 10/51924-0, 11/07366-5)
ARITA, JULIANA HARUMI; BARROS, MARIO H.; RAVAGNANI, FELIPE GUSTAVO; ZIOSI, MARCELLO; SANCHES, LIVIA RENTAS; PICOSSE, FABIOLA ROSA; LOPES, TANIA OLIVEIRA; AGUIAR, PATRICIA DE CARVALHO; MACABELLI, CAROLINA HABERMANN; CHIARATTI, MARCOS R.; et al. Metabolic studies of a patient harbouring a novel S487L mutation in the catalytic subunit of AMPK. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v. 1864, n. 5, p. 8-pg., . (10/51924-0, 13/07937-8, 11/07366-5, 15/23549-3)

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