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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Membrane damage by betulinic acid provides insights into cellular aging

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Autor(es):
Martins, Waleska K. ; Gomide, Andreza B. ; Costa, Erico T. ; Junqueira, Helena C. ; Stolf, Beatriz S. ; Itri, Rosangela ; Baptista, Mauricio S.
Número total de Autores: 7
Tipo de documento: Artigo Científico
Fonte: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1861, n. 1, A, p. 3129-3143, JAN 2017.
Citações Web of Science: 2
Resumo

Background: Cell senescence is a process of central importance to the understanding of aging as well as to the development of new drugs. It is related with genomic instability, which has been shown to occur in the presence of autophagy deficiency. Yet, the mechanism that triggers genomic instability and senescence from a condition of autophagy deficiency remains unknown. By analyzing the consequences of treating human keratinocytes (HaCaT) with the pentacyclic triterpenoid Betulinic Acid (BA) we were able to propose that cell senescence can develop as a response to parallel damage in the membranes of mitochondria and lysosome. Methods: We performed biochemical, immunocytochemical and cytometric assays after challenging HaCaT cells with BA. We also evaluated membrane leakage induced by BA in liposomes and giant unilamellar vesicles. Results: By destabilizing lipid bilayers of mitochondria and lysosomes, BA triggers the misbalance in the mitochondrial-lysosomal axis leading to perceived autophagy impairment, lipofuscinogenesis, genomic instability and cell senescence. The progressive accumulation of mitochondria and lipofuscin, which comes from imperfect mitophagy triggered by BA, provides a continuous source of reactive species further damaging lysosomes and leading to cell aging. Conclusions: This work reveals that the initial trigger of cell senescence can be the physical damage in the membranes of lysosomes and mitochondria. General significance: This concept will help in the search of new drugs that act as senescence-inductors. BA is under evaluation as chemotherapeutic agent against several types of tumors and induction of cell senescence should be considered as one of its main mechanisms of action. (C) 2016 Elsevier B.V. All rights reserved. (AU)

Processo FAPESP: 13/07937-8 - Redoxoma
Beneficiário:Ohara Augusto
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 12/50680-5 - Fotossensibilização nas ciências da vida
Beneficiário:Mauricio da Silva Baptista
Linha de fomento: Auxílio à Pesquisa - Temático