title: Membrane damage by betulinic acid provides insights into cellular aging.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  This work reveals that the initial trigger of cell senescence can be the physical damage in the membranes of lysosomes and mitochondria.
  
  
  
  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.
authors: Instituto de Química, Universidade de São Paulo, Brazil; Universidade de Santo Amaro, Brazil.
authors: Waleska K
authors: WK
authors: Martins
authors: Instituto de Física, Universidade de São Paulo, Brazil; Centro Universitário Padre Anchieta, Brazil.
authors: Andreza B
authors: AB
authors: Gomide
authors: Ludwig Institute for Cancer Research (LICR) at Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil.
authors: Érico T
authors: ÉT
authors: Costa
authors: Instituto de Química, Universidade de São Paulo, Brazil.
authors: Helena C
authors: HC
authors: Junqueira
authors: Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil.
authors: Beatriz S
authors: BS
authors: Stolf
authors: Instituto de Física, Universidade de São Paulo, Brazil.
authors: Rosangela
authors: R
authors: Itri
authors: Instituto de Química, Universidade de São Paulo, Brazil. Electronic address: baptista@iq.usp.br.
authors: Maurício S
authors: MS
authors: Baptista
mesh_terms: D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D008062:Lipofuscin / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology*; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism; D000094062:Betulinic Acid
chemical_list: D008062:Lipofuscin; D008081:Liposomes; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid
keywords: Autophagy impairment; Lipofuscinogenesis; Membrane biophysics; Redox misbalance; Senescence, Mitochondrial-lysosomal axis theory of aging