Parallel damage in mitochondrial and lysosomal compartments promotes efficient cell death with autophagy: The case of the pentacyclic triterpenoids

Autor(es)

Martins, Waleska K. ^[1] ; Costa, Erico T. ^[2] ; Cruz, Mario C. ^[3] ; Stolf, Beatriz S. ^[3] ; Miotto, Ronei ^[4] ; Cordeiro, Rodrigo M. ^[4] ; Baptista, Mauricio S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, BR-05508 Sao Paulo - Brazil

^[2] Hosp Sirio Libanes, LICR, Ctr Oncol Mol, Sao Paulo - Brazil

^[3] Univ Sao Paulo, Inst Ciencias Biomed, BR-05508 Sao Paulo - Brazil

^[4] UF ABC, Ctr Ciencias Nat & Humanas, Santo Andre, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 5, JUL 27 2015.
• Citações Web of Science: 13

Resumo

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. (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