Mitochondrial damage as an early event of monensin-induced cell injury in cultured fibroblasts L929.
The present study was designed to identify, submicroscopically, the primary organelle or target structure for monensin in cultured murine fibroblasts L929. In addition, the effect of the drug on cell size and surface membranes of the cells were analysed; cellular proliferation, collagen secretion, and necrosis and apoptosis were re-evaluated. At the lowest concentration of monensin the foremost ultrastructural alteration occurred in the mitochondria, characterized by increased matrix density with disorganized and less distinct crystae. Incubation with monensin at higher concentrations resulted in severe mitochondrial damage and marked dilatation of the Golgi apparatus and rough endoplasmic reticulum cisternae. Fibroblasts exposed to higher concentrations of monensin were enlarged with decreased number of filopodia and hollows in the surface membrane. Moreover, monensin inhibited the cell proliferation, increased immunohistochemical positiveness for collagen type I in a dose-dependent manner, and, at high concentrations, caused cell necrosis whereas apoptosis was not induced. Taken together, these results show that monensin induces early mitochondrial damage, possibly causing an energy deficit that led to inhibition of fibroblasts proliferation and accumulation of collagen causing dilatation of Golgi apparatus and rough endoplasmic reticulum. Moreover, the mitochondrial damage would also explain the monensin-induced necrosis.
Souza
A C
AC
Department of Pathology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, 14049-900 Ribeirao Preto, SP, Brazil.
Machado
F S
FS
Celes
M R N
MR
Faria
G
G
Rocha
L B
LB
Silva
J S
JS
Rossi
M A
MA
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000648:ultrastructure; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005354:Fibrosarcoma / Q000473:pathology; D006056:Golgi Apparatus / Q000187:drug effects / Q000648:ultrastructure; D007150:Immunohistochemistry; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects* / Q000648:ultrastructure; D008985:Monensin / Q000008:administration & dosage / Q000494:pharmacology*
D008985:Monensin