Mitochondrial perturbation attenuates bile acid-induced cytotoxicity

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.

Bile acids inhibit Na+/H+ exchanger and Cl−/HCO3 − exchanger activities via cellular energy breakdown and Ca2+ overload in human colonic crypts

“…Since previous works have reported that BA can disrupt intracellular organelles (mitochondria, or Golgi) [4,29,31], we first analysed the structure of the cell compartments of human colonic epithelial cells following 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 incubation with BA. Transmission electron microscopy (TEM) revealed that administration of low concentrations of CDC (0.1mM or 0.3mM) for 1-10 min had no effect on the structure of intracellular organelles (Fig.…”

Cancer and age related colonic crypt deficiencies in cytochromecoxidase I

“…When cells of human colonic origin (HCT116) were treated with the bile acid deoxycholate (0.5 mmol/L) for 4 h, the majority of cells entered apoptosis. However pretreatment of the cells with sodium azide, which binds to CcO and inhibits the protein complex from functioning, significantly reduced the fraction of cells undergoing apoptosis upon further treatment with deoxycholate [22] , indicating that CcO deficient cells are resistant to induction of apoptosis. We previously showed that reduction in CcOI expression correlated with a reduction in apoptotic competence in nearby tissue samples from the same colonic epithelium [6] .…”

Bile acids in combination with low pH induce oxidative stress and oxidative DNA damage: relevance to the pathogenesis of Barrett's oesophagus

“…5 Patients taking proton pump inhibitors have a significantly higher incidence of overgrowth of gastric bacteria and, consequently, increased concentrations of unconjugated bile acids, including DCA. 10 Bile acids induce mitochondrial alterations, [11][12][13] oxidative stress 11 12 14 15 and DNA damage. [14][15][16] We have also shown that perturbation of mitochondria can lead to apoptosis resistance.…”