Lack of oxidative phosphorylation and low mitochondrial membrane potential decrease susceptibility to apoptosis and do not modulate the protective effect of Bcl-xL in osteosarcoma cells

Department of Neurology, University of Miami, School of Medicine, Miami, Florida 33136, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2000; 275(10):7087-94.
Source: PubMed


We explored the role of low mitochondrial membrane potential (DeltaPsim) and the lack of oxidative phosphorylation in apoptosis by assessing the susceptibility of osteosarcoma cell lines with and without mitochondrial DNA to staurosporine-induced death. Our cells without mitochondrial DNA had low DeltaPsim and no functional oxidative phosphorylation. Contrary to our expectation, these cells were more resistant to staurosporine-induced death than were the parental cells. This reduced susceptibility was associated with decreased activation of caspase 3 but not with the mitochondrial permeability transition pore or cytochrome c release from the mitochondria. Apoptosis in both cell lines was associated with an increase in DeltaPsim. Bcl-x(L) could protect both cell types against caspase 3 activation and apoptosis by a mechanism that does not appear to be mediated by mitochondrial function or modulation of DeltaPsim. Nevertheless, we found that Bcl-x(L) expression can stimulate cell respiration in cells with mitochondrial DNA. Our results showed that the lack of functional oxidative phosphorylation and/or low mitochondrial membrane potential are associated with an antiapoptotic effect, possibly contributing to the development of some types of cancer. It also reinforces a model in which Bcl-x(L) can exert an antiapoptotic effect by stimulating oxidative phosphorylation and/or inhibiting caspase activation.

1 Read
  • Source
    • "Collectively, lipid metabolism in cancer cells was context dependent and would generate intricate connections in cancer reprogramming metabolism. Mitochondrial function was another core part of cancer metabolism [3] [4] [5] [6] and was also implied in many aspects, including therapeutic resistance [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17], autophagy [18] [19] [20] [21], drug sensitivity [22] [23] [24], apoptosis [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38], metastasis [39] [40] [41] [42], and angiogenesis [43]. Mitochondrial function was regarded as a metabolic symbiosis between tumor stromal cells and epithelial cancer cells in human breast cancer [5]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Berberine interfering with cancer reprogramming metabolism was confirmed in our previous study. Lipid metabolism and mitochondrial function were also the core parts in reprogramming metabolism. In the presence of some energy-related inhibitors, including C75, compound C, and TOFA, the discrete roles of berberine in lipid metabolism and mitochondrial function were elucidated. An altered lipid metabolism induced by berberine was observed under the inhibition of FASN, AMPK, and ACC in breast cancer cell MCF-7. And the reversion of berberine-induced lipid suppression indicated that ACC inhibition might be involved in that process instead of FASN inhibition. A robust apoptosis induced by berberine even under the inhibition of AMPK and lipid synthesis was also indicated. Finally, mitochondrial function regulation under the inhibition of AMPK and ACC might be in an ACL-independent manner. Undoubtedly, the detailed mechanisms of berberine interfering with lipid metabolism and mitochondrial function combined with energy-related inhibitors need further investigation, including the potential compensatory mechanisms for ATP production and the upregulation of ACL.
    Evidence-based Complementary and Alternative Medicine 09/2015; 2015(5):396035. DOI:10.1155/2015/396035 · 1.88 Impact Factor
    • "The Leishmania promastigotes were subjected to treatment with CopNEC-AmB, AmB, CopNEC and Cop for different time points (0, 6, 24 and 48 h), incubated for 7 min with 10 mM JC-1 (Sigma-Aldrich) at 37°C, washed and resuspended in medium. The relative mitochondrion potential (Δψm) value was calculated from the ratio of fluorescence at 590 to 530 nm (Dey and Moraes, 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: To improve oral delivery of AmB by achieving increased oral bioavailability and synergistically enhanced antileishmanial activity using copaiba oil (Cop) through nano-emulsified carrier system (CopNEC). The AmB encapsulated nano-emulsified carrier (CopNEC-AmB) comprised of Cop, d-alpha Tocopheryl Polyethylene Glycol 1000 Succinate and phosphatidylcholine was prepared by high pressure homogenization method. Stability study of CopNEC-AmB was carried out in simulated gastric fluid and simulated intestinal fluid. The CopNEC-AmB and plain AmB were compared for in vitro antileishmanial activity, their pharmacokinetics, organ distribution and toxicity profiling. The optimized CopNEC-AmB has globule size of 127±21 nm, PDI 0.11±0.02, and zeta potential (-)38.5±2.7 with encapsulation efficiency 91.9±1.4 %w/w. The high resolution transmission electron microscopy illustrates spherical particle geometry with homogeny in their sizes. The optimized CopNEC-AmB was found to be stable in gastro-intestinal fluids showing insignificant changes in globule size and encapsulation efficiency. The AUC0-48 value of CopNEC-AmB in rats was significantly improved showing 7.2 folds higher oral bioavailability than free drug. The in vitro antileishmanial activity of CopNEC-AmB was significantly higher (p<0.05) than the free drug because copaiba oil synergistically enhanced chemotherapy of leishmaniasis by causing drastic changes in morphology of Leishmania parasite and rupture of the plasma membrane with loss of their contents. The CopNEC-AmB showed significantly lesser hemolytic toxicity and cell cytotoxicity, and absence of any changes in histopathology of kidney tissues as compared to free drug. This prototype CopNEC formulation showed improved bioavailability and nontoxic synergistic antileishmanial chemotherapy of AmB due to copaiba oil against leishmaniasis. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 03/2015; 172(14). DOI:10.1111/bph.13149 · 4.84 Impact Factor
  • Source
    • "Mitochondrial membrane potential determination. The mitochondrial membrane potential (DYm) was monitored by using JC-1 dye as a probe (Dey & Moraes, 2000). JC-1 is a cationic mitochondrial vital dye that is lipophilic and becomes concentrated in the mitochondria in proportion to DYm: more dye accumulates in mitochondria with a greater DYm and ATP-generating capacity (Sudhandiran & Shaha, 2003). "

Show more