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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Membrane damage by betulinic acid provides insights into cellular aging

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Martins, Waleska K. ; Gomide, Andreza B. ; Costa, Erico T. ; Junqueira, Helena C. ; Stolf, Beatriz S. ; Itri, Rosangela ; Baptista, Mauricio S.
Total Authors: 7
Document type: Journal article
Source: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1861, n. 1, A, p. 3129-3143, JAN 2017.
Web of Science Citations: 3

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)

FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
Grantee:Ohara Augusto
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 12/50680-5 - Photosensitization in life sciences
Grantee:Mauricio da Silva Baptista
Support type: Research Projects - Thematic Grants