Mitochondrial perturbation attenuates bile acid-induced cytotoxicity.
Hydrophobic bile acids such as deoxycholate (DOC) are known to damage liver cells during cholestasis and promote colon cancer. Cellular stresses induced by bile acids, which include mitochondrial and endoplasmic reticulum (ER) stresses, can result in apoptosis. We found that inhibition of mitochondrial complexes I-V with rotenone, thenoyltrifluoroacetone (TTFA), antimycin A, myxothiazol or oligomycin strongly protected against DOC-induced apoptosis of HCT-116 cells. To understand the mechanism of this protection, we explored the ability of these specific inhibitors to reduce DOC-induced mitochondrial and ER stresses. Different inhibitors markedly reduced DOC-induction of mitochondrial condensation, the DOC-induced decrease in mitochondrial membrane potential and the DOC-induced dilatation of the ER (evidence of ER stress). A dramatic induction of nucleolar segregation by antimycin A and myxothiazol, two distinct complex III inhibitors, was also observed. These findings strongly implicate mitochondrial crosstalk with apoptotic signaling pathways and mitochondrial-nucleolar crosstalk in the development of apoptosis resistance in the colon.
Payne
C M
CM
Department of Cell Biology and Anatomy, University of Arizona, Tucson, 85724, USA. cpayne@email.arizona.edu
Crowley-Weber
C L
CL
Dvorak
K
K
Bernstein
C
C
Bernstein
H
H
Holubec
H
H
Crowley
C
C
Garewal
H
H
D000968:Antimycin A / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001647:Bile Acids and Salts / Q000633:toxicity; D002466:Cell Nucleolus / Q000187:drug effects / Q000648:ultrastructure; D003840:Deoxycholic Acid / Q000633:toxicity*; D014450:Electron Transport Complex III / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000648:ultrastructure; D045325:HCT116 Cells; D006801:Humans; D008564:Membrane Potentials; D008689:Methacrylates / Q000494:pharmacology; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D008933:Mitochondrial Swelling; D009840:Oligomycins / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014475:Uncoupling Agents / Q000494:pharmacology
D001647:Bile Acids and Salts; D008689:Methacrylates; D009840:Oligomycins; D013844:Thiazoles; D014475:Uncoupling Agents; D003840:Deoxycholic Acid; D000968:Antimycin A; C030517:myxothiazol; D025261:Mitochondrial Proton-Translocating ATPases; D014450:Electron Transport Complex III