title: Parallel damage in mitochondrial and lysosomal compartments promotes efficient cell death with autophagy: The case of the pentacyclic triterpenoids.
abstract: The role of autophagy in cell death is still controversial and a lot of debate has concerned the transition from its pro-survival to its pro-death roles. The similar structure of the triterpenoids Betulinic (BA) and Oleanolic (OA) acids allowed us to prove that this transition involves parallel damage in mitochondria and lysosome. After treating immortalized human skin keratinocytes (HaCaT) with either BA or OA, we evaluated cell viability, proliferation and mechanism of cell death, function and morphology of mitochondria and lysosomes, and the status of the autophagy flux. We also quantified the interactions of BA and OA with membrane mimics, both in-vitro and in-silico. Essentially, OA caused mitochondrial damage that relied on autophagy to rescue cellular homeostasis, which failed upon lysosomal inhibition by Chloroquine or Bafilomycin-A1. BA caused parallel damage on mitochondria and lysosome, turning autophagy into a destructive process. The higher cytotoxicity of BA correlated with its stronger efficiency in damaging membrane mimics. Based on these findings, we underlined the concept that autophagy will turn into a destructive outcome when there is parallel damage in mitochondrial and lysosomal membranes. We trust that this concept will help the development of new drugs against aggressive cancers.
authors.affiliation: Instituto de Química, Universidade de São Paulo, Brazil.
authors.forename: Waleska K
authors.initials: WK
authors.lastname: Martins
authors.affiliation: Ludwig Institute for Cancer Research (LICR) at Centro de Oncologia Molecular, Hospital Sírio Libanês, São Paulo, Brazil.
authors.forename: Érico T
authors.initials: ÉT
authors.lastname: Costa
authors.affiliation: Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil.
authors.forename: Mário C
authors.initials: MC
authors.lastname: Cruz
authors.affiliation: Instituto de Ciências Biomédicas, Universidade de São Paulo, Brazil.
authors.forename: Beatriz S
authors.initials: BS
authors.lastname: Stolf
authors.affiliation: Centro de Ciências Naturais e Humanas, UF-ABC, Brazil.
authors.forename: Ronei
authors.initials: R
authors.lastname: Miotto
authors.affiliation: Centro de Ciências Naturais e Humanas, UF-ABC, Brazil.
authors.forename: Rodrigo M
authors.initials: RM
authors.lastname: Cordeiro
authors.affiliation: Instituto de Química, Universidade de São Paulo, Brazil.
authors.forename: Maurício S
authors.initials: MS
authors.lastname: Baptista
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008247:Lysosomes / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D053978:Pentacyclic Triterpenes / Q000008:administration & dosage*
chemical_list: D053978:Pentacyclic Triterpenes