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Apoptosis

, Volume 10, Issue 4, pp 841–850 | Cite as

Ceramide induces mitochondrial abnormalities in insulin-secreting INS-1 cells: Potential mechanisms underlying ceramide-mediated metabolic dysfunction of the β cell

  • R. Veluthakal
  • R. Palanivel
  • Y. Zhao
  • P. McDonald
  • S. Gruber
  • A. KowluruEmail author
Article

C2-ceramide, a cell permeable analogue of ceramide [CER] markedly reduced mitochondrial membrane potential [MMP] in insulin-secreting INS cells, which was followed by a significant accumulation of cytochrome c [Cyt c] into the cytosolic compartment. In a manner akin to CER, exposure of these cells to interleukin-1β [IL-1β] also resulted in reduction in MMP and cytosolic accumulation of Cyt c. Further, long-term exposure of these cells to either CER [but not its inactive analogue] or IL-1β caused a marked reduction in their metabolic viability. However, unlike IL-1β, which increased nitric oxide [NO] release, CER-treatment of INS cells had no effects of CER on NO release were demonstrable. Together, these findings suggest that CER-induced mitochondrial effects may not be mediated via iNOS gene expression and NO production. CER also activated an okadaic acid -sensitive protein phosphatase [CAPP] in the purified mitochondrial fraction, suggesting that CAPP might represent one of the target proteins for CER in the β cell mitochondria. Together, our findings suggest direct detrimental effects of CER on mitochondrial function in β cells leading to their dysfunction and demise via apoptosis. Moreover, our findings provide evidence for a potential difference in the mechanisms underlying CER- and IL-1β-induced mitochondrial defects and apoptotic demise of the effete β cell.

Keywords

apoptosis ceramide mitochondria pancreatic β cell protein phosphatase 

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • R. Veluthakal
    • 1
  • R. Palanivel
    • 1
    • 3
  • Y. Zhao
    • 1
  • P. McDonald
    • 3
  • S. Gruber
    • 2
  • A. Kowluru
    • 2
    Email author
  1. 1.Department of Pharmaceutical Sciences3601, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State UniversityDetroit
  2. 2.Wayne State UniversityDetroit
  3. 3.John D. Dingell VA Medical CenterDetroit

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