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Mitochondrial perturbation attenuates bile acid-induced cytotoxicity

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Abstract

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.

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Abbreviations

DOC:

deoxycholate

ER:

endoplasmic reticulum

GI:

gastrointestinal

MMP:

mitochondrial membrane potential

NaN3 :

sodium azide

ROS:

reactive oxygen species

TEM:

transmission electron microscopy

TTFA:

thenoyltrifluoroacetone

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Authors and Affiliations

  1. Department of Cell Biology and Anatomy, University of Arizona, Tucson, Arizona

    C. M. Payne (Ph.D.), C. L. Crowley-Weber, K. Dvorak, C. Bernstein, H. Bernstein, H. Holubec, C. Crowley & H. Garewal

  2. Arizona Cancer Center, University of Arizona, Tucson, Arizona

    C. M. Payne (Ph.D.), K. Dvorak, H. Bernstein & H. Garewal

  3. Department of Internal Medicine, University of Arizona, Tucson, Arizona

    H. Garewal

  4. Section of Hematology/Oncology, Southern Arizona Veterans Affairs Health Care System, Tucson, Arizona, USA

    H. Garewal

  5. Department of Cell Biology and Anatomy, College of Medicine, University of Arizona, Tucson, AZ, 85724-5044, USA

    C. M. Payne (Ph.D.)

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  1. C. M. Payne
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Payne, C.M., Crowley-Weber, C.L., Dvorak, K. et al. Mitochondrial perturbation attenuates bile acid-induced cytotoxicity. Cell Biol Toxicol 21, 215–231 (2005). https://doi.org/10.1007/s10565-005-0166-6

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