CoChat
Sign Up
Cited by 32

The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.

Parallel damage in mitochondrial and lysosomal compartments promotes efficient cell death with autophagy: The case of the pentacyclic triterpenoids

Martins, Waleska K., Costa, Érico T., Cruz, Mário C., Stolf, Beatriz S., Miotto, Ronei, Cordeiro, Rodrigo M., Baptista, Maurício S.·2015·Scientific Reports
DOI 10.1038/srep12425PMC PMC4515638
Open this paper in CoChat — free account

Abstract

The role of autophagy in cell death is still controversial and a lot of debate has concerned the transition from its pro-survival to its pro-death roles. The similar structure of the triterpenoids Betulinic (BA) and Oleanolic (OA) acids allowed us to prove that this transition involves parallel damage in mitochondria and lysosome. After treating immortalized human skin keratinocytes (HaCaT) with either BA or OA, we evaluated cell viability, proliferation and mechanism of cell death, function and morphology of mitochondria and lysosomes and the status of the autophagy flux. We also quantified the interactions of BA and OA with membrane mimics, both in-vitro and in-silico. Essentially, OA caused mitochondrial damage that relied on autophagy to rescue cellular homeostasis, which failed upon lysosomal inhibition by Chloroquine or Bafilomycin-A1. BA caused parallel damage on mitochondria and lysosome, turning autophagy into a destructive process. The higher cytotoxicity of BA correlated with its stronger efficiency in damaging membrane mimics. Based on these findings, we underlined the concept that autophagy will turn into a destructive outcome when there is parallel damage in mitochondrial and lysosomal membranes. We trust that this concept will help the development of new drugs against aggressive cancers.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/srep12425

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Show all 6 references

Research works printed but not linked: 43

  1. Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008). · DOI · Paper page
  2. Vessoni, A. T., Filippi-Chiela, E. C., Menck, C. F. & Lenz, G. Autophagy and genomic integrity. Cell Death Differ. 20, 1444–54 (2013). · DOI
  3. Brunk, U. T. & Terman, A. The mitochondrial-lysosomal axis theory of aging: Accumulation of damaged mitochondria as a result of imperfect autophagocytosis. Eur. J. Biochem. 269, 1996–2002 (2002). · DOI
  4. Terman, A., Gustafsson, B. & Brunk, U. T. Autophagy, organelles and ageing. Journal of Pathology 211, 134–143 (2007). · DOI
  5. Boukamp, P. et al. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J. Cell Biol. 106, 761–71 (1988). · DOI · Paper page
  6. Aymard, E. et al. Autophagy in human keratinocytes: an early step of the differentiation? Exp. Dermatol. 20, 263–8 (2011). · DOI
  7. Martins, W. K., Severino, D., Souza, C., Stolf, B. S. & Baptista, M. S. Rapid screening of potential autophagic inductor agents using mammalian cell lines. Biotechnol. J. 8, 730–737 (2013). · DOI · Paper page
  8. Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 4, 151–175 (2008). · DOI · Paper page
  9. Fontanay, S., Grare, M., Mayer, J., Finance, C. & Duval, R. E. Ursolic, oleanolic and betulinic acids: antibacterial spectra and selectivity indexes. J. Ethnopharmacol. 120, 272–6 (2008). · DOI
  10. Dzubak, P. et al. Pharmacological activities of natural triterpenoids and their therapeutic implications. Nat. Prod. Rep. 23, 394–411 (2006). · DOI
  11. Fulda, S. Betulinic acid: a natural product with anticancer activity. Mol. Nutr. Food Res. 53, 140–146 (2009). · DOI
  12. Fulda, S. et al. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J. Biol. Chem. 273, 33942–8 (1998). · DOI
  13. Mullauer, F. B., Kessler, J. H. & Medema, J. P. Betulinic acid induces cytochrome c release and apoptosis in a Bax/Bak-independent, permeability transition pore dependent fashion. Apoptosis 14, 191–202 (2009). · DOI
  14. Fulda, S. & Kroemer, G. Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov. Today 14, 885–90 (2009). · DOI
  15. Potze, L., Mullauer, F. B., Colak, S., Kessler, J. H. & Medema, J. P. Betulinic acid-induced mitochondria-dependent cell death is counterbalanced by an autophagic salvage response. Cell Death Dis. 5, e1169 (2014). · DOI
  16. Raghuvar Gopal, D. V., Narkar, A. a., Badrinath, Y., Mishra, K. P. & Joshi, D. S. Betulinic acid induces apoptosis in human chronic myelogenous leukemia (CML) cell line K-562 without altering the levels of Bcr-Abl. Toxicol. Lett. 155, 343–351 (2005). · DOI
  17. Yang, L. et al. Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro. Acta Pharmacol. Sin. 33, 1542–8 (2012). · DOI
  18. Gonzalez, P. et al. Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process. Cell Death Differ. 19, 1337–46 (2012). · DOI
  19. Laszczyk, M. N. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med. 75, 1549–60 (2009). · DOI
  20. Haass, N. K., Smalley, K. S. M., Li, L. & Herlyn, M. Adhesion, migration and communication in melanocytes and melanoma. Pigment Cell Res. 18, 150–9 (2005). · DOI
  21. Ding, W. X. et al. Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J. Biol. Chem. 285, 27879–27890 (2010). · DOI · Paper page
  22. Mofarrahi, M. et al. Autophagic flux and oxidative capacity of skeletal muscles during acute starvation. Autophagy 9, 1604–1620 (2013). · DOI
  23. Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010). · DOI · Paper page
  24. Moriyama, Y. & Nelson, N. H+-transloaction ATP in Golgi apparatus. Characterization as vacuolar H+-ATPase and its subunit structures. Journal of Biological Chemistry 264, 18445–18450 (1989). · DOI
  25. Lemasters, J. J. Variants of mitochondrial autophagy: Types 1 and 2 mitophagy and micromitophagy (Type 3). Redox Biology 2, 749–754 (2014). · DOI
  26. Repnik, U., Hafner Česen, M. & Turk, B. Lysosomal membrane permeabilization in cell death: Concepts and challenges. Mitochondrion (2014). 10.1016/j.mito.2014.06.006 · DOI
  27. Yoon, Y. H. et al. Induction of lysosomal dilatation, arrested autophagy and cell death by chloroquine in cultured ARPE-19 cells. Investig. Ophthalmol. Vis. Sci. 51, 6030–6037 (2010). · DOI · Paper page
  28. Pivtoraiko, V. N. et al. Low-dose bafilomycin attenuates neuronal cell death associated with autophagy-lysosome pathway dysfunction. J. Neurochem. 114, 1193–204 (2010). · DOI
  29. Csuk, R. Betulinic acid and its derivatives: a patent review (2008 - 2013). Expert Opin. Ther. Pat. 24, 913–23 (2014). · DOI
  30. Lúcio, K. A. et al. Oleanolic acid initiates apoptosis in non-small cell lung cancer cell lines and reduces metastasis of a B16F10 melanoma model in vivo. PLoS One 6, e28596 (2011). · DOI
  31. Terman, A., Kurz, T., Navratil, M., Arriaga, E. A. & Brunk, U. T. Mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondrial-lysosomal axis theory of aging. Antioxid. Redox Signal. 12, 503–535 (2010). · DOI · Paper page
  32. Broniatowski, M., Flasiński, M. & Wydro, P. Investigation of the interactions of lupane type pentacyclic triterpenes with outer leaflet membrane phospholipids - Langmuir monolayer and synchrotron X-ray scattering study. J. Colloid Interface Sci. 381, 116–124 (2012). · DOI
  33. Chen, Y., Sun, R. & Wang, B. Monolayer behavior of binary systems of betulinic acid and cardiolipin: thermodynamic analyses of Langmuir monolayers and AFM study of Langmuir-Blodgett monolayers. J. Colloid Interface Sci. 353, 294–300 (2011). · DOI
  34. Gao, M., Lau, P. M. & Kong, S. K. Mitochondrial toxin betulinic acid induces in vitro eryptosis in human red blood cells through membrane permeabilization. Arch. Toxicol. 88, 755–68 (2014).
  35. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). · DOI · Paper page
  36. Evans, V. J., Earle, W. R., Sanford, K. K., Shannon, J. E. & Waltz, H. K. The preparation and handling of replicate tissue cultures for quantitative studies. J. Natl. Cancer Inst. 11, 907–927 (1951).
  37. Galluzzi, L. et al. Methods for the assessment of mitochondrial membrane permeabilization in apoptosis. Apoptosis 12, 803–13 (2007). · DOI
  38. Pendergrass, W., Wolf, N. & Poot, M. Efficacy of MitoTracker Green and CMXrosamine to measure changes in mitochondrial membrane potentials in living cells and tissues. Cytometry. A 61, 162–9 (2004). · DOI
  39. Au, S., Weiner, N. D. & Schacht, J. Aminoglycoside antibiotics preferentially increase permeability in phosphoinositide-containing membranes: a study with carboxyfluorescein in liposomes. Biochim. Biophys. Acta 902, 80–6 (1987). · DOI
  40. Hess, B., Kutzner, C., Van Der Spoel, D. & Lindahl, E. GRGMACS 4: Algorithms for highly efficient, load-balanced and scalable molecular simulation. J. Chem. Theory Comput. 4, 435–447 (2008). · DOI
  41. Van Der Spoel, D. et al. GROMACS: fast, flexible and free. J. Comput. Chem. 26, 1701–18 (2005). · DOI
  42. Poger, D. & Mark, A. E. On the Validation of Molecular Dynamics Simulations of Saturated and cis -Monounsaturated Phosphatidylcholine Lipid Bilayers: A Comparison with Experiment. J. Chem. Theory Comput. 6, 325–336 (2010). · DOI
  43. Oostenbrink, C., Villa, A., Mark, A. E. & van Gunsteren, W. F. A biomolecular force field based on the free enthalpy of hydration and solvation: the GROMOS force-field parameter sets 53A5 and 53A6. J. Comput. Chem. 25, 1656–76 (2004). · DOI

Cited by

Sorted by citations

See all 32

Metadata

Authors
Martins, W. K., Costa, É. T., Cruz, M. C., Stolf, B. S., Miotto, R., Cordeiro, R. M., & Baptista, M. S.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2015-07-27
Volume
5
Issue
1
ISSN
2045-2322
DOI
10.1038/srep12425
PMC
PMC4515638
Cited by
32
References
6
Language
en
Licence

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review