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Edelfosine and perifosine disrupt hepatic mitochondrial oxidative phosphorylation and induce the permeability

Ana Burgeiro1, Cláudia V Pereira, Filipa S Carvalho

  • 1CNC - Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal.

Mitochondrion
|November 21, 2012
PubMed

Insights

Edelfosine and perifosine, potential anticancer drugs, disrupt mitochondrial function by inhibiting respiration and altering membrane permeability. These alkylphospholipids induce mitochondrial permeability transition, impacting cellular energy production and potentially causing toxicity in non-tumor tissues.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Edelfosine and perifosine are alkylphospholipids investigated as anticancer agents.
  • Their apoptotic effects are partially mediated through mitochondria.
  • Previous studies indicated edelfosine alters mitochondrial membrane permeability, a process modulated by cyclosporin A.

Purpose of the Study:

  • To confirm mitochondrial permeability transition induced by edelfosine and perifosine.
  • To identify direct effects of these ether lipids on hepatic mitochondrial fractions.
  • To investigate impacts on mitochondrial oxidative phosphorylation and hydrogen peroxide (H(2)O(2)) generation.

Main Methods:

  • Isolated hepatic mitochondrial fractions were used.
  • Mitochondrial respiration, transmembrane electric potential, and H(2)O(2) production were measured.
  • Effects of edelfosine and perifosine were assessed under various conditions.

Main Results:

  • Both edelfosine and perifosine inhibited mitochondrial respiration and decreased transmembrane electric potential.
  • These compounds induced mitochondrial permeability transition even in non-energized mitochondria.
  • Edelfosine specifically reduced H(2)O(2) production via the respiratory chain.

Conclusions:

  • Edelfosine and perifosine induce previously unrecognized alterations in mitochondrial physiology.
  • These findings clarify the mitochondrial-targeting mechanisms of these compounds.
  • The results highlight potential toxic effects in non-tumor organs due to mitochondrial interactions.

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