Role of mitochondrial complexes I and II, reactive oxygen species and arachidonic acid metabolism in deoxycholate-induced apoptosis

Washo-Stultz, Delon; Crowley-Weber, Cara L; Dvořáková, Kateřina; Bernstein, Carol; Bernstein, Harris; Kunke, Kathleen; Waltmire, Caroline N.; Garewal, Harinder S.; Payne, Claire M.

doi:10.1016/s0304-3835(01)00786-8

Cited by 52 publications

(41 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…46). Bile acids also damage mitochondria (47,48), resulting in increased oxidative stress (49) and reduced mitochondrial membrane potential (47,50,51).…”

Section: Discussionmentioning

confidence: 99%

Crypt-Restricted Loss and Decreased Protein Expression of Cytochrome c Oxidase Subunit I as Potential Hypothesis-Driven Biomarkers of Colon Cancer Risk

Payne¹,

Holubec²,

Bernstein³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

Self Cite

View full text Add to dashboard Cite

There is an increasing demand for the development of intermediate biomarkers to assess colon cancer risk. We previously determined that a live cell bioassay, which assesses apoptosis resistance in the nonneoplastic colonic mucosa, detects f50% of patients with colon cancer. A hypothesis-driven biomarker that reflects apoptosis resistance in routine formalin-fixed, paraffin-embedded tissue would be easier to use. Cytochrome c oxidase is a critical enzyme that controls mitochondrial respiration and is central to apoptosis. We did an immunohistochemical study of cytochrome c oxidase subunit I expression in 46 colonic mucosal samples from 16 patients who had undergone a colonic resection. These included five patients without evidence of colonic neoplasia (three normal and two diverticulitis), three patients with tubulovillous adenomas, and eight patients with colonic adenocarcinomas. Analysis of aberrancies in expression of cytochrome c oxidase subunit I showed that, compared with nonneoplasia, the patients with neoplasia had a higher mean incidence of crypts having decreased expression (1.7 versus 22.8, P = 0.03) and a higher mean incidence having crypt-restricted loss (0.6 versus 3.2, P = 0.06). The percentage with segmented loss was low and was similar in the two groups. Combining these results, the mean % normal (i.e., with none of the three types of abnormality) was 96.7 in nonneoplasia versus only 73.2 in patients with neoplasia (P = 0.02).

show abstract

“…46). Bile acids also damage mitochondria (47,48), resulting in increased oxidative stress (49) and reduced mitochondrial membrane potential (47,50,51).…”

Section: Discussionmentioning

confidence: 99%

Crypt-Restricted Loss and Decreased Protein Expression of Cytochrome c Oxidase Subunit I as Potential Hypothesis-Driven Biomarkers of Colon Cancer Risk

Payne¹,

Holubec²,

Bernstein³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hydrophobic bile acids perturb mitochondrial function (Krahenbuhl et al, 1992;Sokol et al, 1995;Rolo et al, 2000;Washo-Stultz et al, 2002;Palmeira and Rolo, 2004), which is believed to contribute to stress-induced apoptosis of hepatocytes (Gores et al, 1998) and colon epithelial cells (Payne et al, 1995b;Garewal et al, Figure 8. Transmission electron micrographs of HCT-116 cells treated with (A) myxothiazol or (B) antimycin A for 24 h. The most dramatic ultrastructural change shared between both of these complex III inhibitors is the presence of nucleolar segregation (NuS).…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that deoxycholate (DOC), a hydrophobic bile acid found in high concentrations in the fecal water of individuals on a typical Western-style high-fat diet (Stadler et al, 1988;Allinger et al, 1989;De Kok et al, 1999), induces apoptosis, in part through a mitochondrial mechanism (Washo-Stultz et al, 2002). A mitochondrial mechanism of DOC-induced apoptosis was indicated by the observation that rotenone and thenoyltrifluoroacetone (TTFA), inhibitors of mitochondrial complexes I ( Barrientos and Moraes, 1999) and II (Ramsay et al, 1981), respectively, reduced DOC-induced apoptosis (Washo-Stultz et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…A mitochondrial mechanism of DOC-induced apoptosis was indicated by the observation that rotenone and thenoyltrifluoroacetone (TTFA), inhibitors of mitochondrial complexes I ( Barrientos and Moraes, 1999) and II (Ramsay et al, 1981), respectively, reduced DOC-induced apoptosis (Washo-Stultz et al, 2002). Such a mechanism was also indicated by the decrease in mitochondrial membrane potential (MMP) in HCT-116 colon epithelial cells (Crowley-Weber et al, 2003) and the formation of megamitochondria within 2-4 h of DOC treatment in HT-29 colon epithelial cells (Washo-Stultz et al, 2002). The underlying mechanism by which rotenone and TTFA decreased apoptosis was suggested to be the prevention of superoxide anion (O − 2 ) formation during cellular respiration.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial perturbation attenuates bile acid-induced cytotoxicity

et al. 2005

View full text Add to dashboard Cite

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.

show abstract

“…Metallothionein 2 appears to transport and release zinc to the inner mitochondrial membrane, thereby inhibiting respiratory chain metabolism, probably by inhibiting mitochondrial complexes I and III [17]. We have recently found that inhibitors of mitochondrial complex I (by rotenone) or complex II (by thenoyltrifluoroacetone) strongly protect HT29 cells from deoxy- cholate-induced apoptosis [18], so that the action of metallothionein 2 in inhibiting the respiratory chain metabolism may be an important protective function by ursodeoxycholate. Ursodeoxycholate protects primary rat hepatic cells and HuH-7 hepatoma cells from deoxycholate-induced apoptosis [19].…”

Section: Discussionmentioning

confidence: 99%

Activation of the Metallothionein IIA Promoter and Other Key Stress Response Elements by Ursodeoxycholate in HepG2 Cells: Relevance to the Cytoprotective Function of Ursodeoxycholate

Bernstein¹,

Payne²,

Bernstein³

et al. 2002

Pharmacology

Self Cite

View full text Add to dashboard Cite

Ursodeoxycholate, used to treat a variety of pathologies, has the ability to reverse cytotoxic and hepatotoxic conditions. We examined HepG2, a hepatic cell line, treated with increasing levels of ursodeoxycholate, for responses of a range of promoters/response elements responsive to DNA damage, heavy metal ions, protein denaturants, aromatic hydrocarbons, retinoids, changes in intracellular AMP levels, end endoplasmic reticulum stress. The metallothionein IIA promoter was the most highly activated by ursodeoxycholate. Since ursodeoxycholate protects against the cytotoxic effects of deoxycholate, our data, combined with observations made by others, implicate metallothionein IIA as being important in this protective pathway.

show abstract

Role of mitochondrial complexes I and II, reactive oxygen species and arachidonic acid metabolism in deoxycholate-induced apoptosis

Cited by 52 publications

References 58 publications

Crypt-Restricted Loss and Decreased Protein Expression of Cytochrome c Oxidase Subunit I as Potential Hypothesis-Driven Biomarkers of Colon Cancer Risk

Crypt-Restricted Loss and Decreased Protein Expression of Cytochrome c Oxidase Subunit I as Potential Hypothesis-Driven Biomarkers of Colon Cancer Risk

Mitochondrial perturbation attenuates bile acid-induced cytotoxicity

Activation of the Metallothionein IIA Promoter and Other Key Stress Response Elements by Ursodeoxycholate in HepG2 Cells: Relevance to the Cytoprotective Function of Ursodeoxycholate

Contact Info

Product

Resources

About