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Lonidamine-induced outer membrane permeability and susceptibility of mitochondria to inhibition by adriamycin
Abstract:
Low concentrations of Adriamycin (ADM) do not inhibit the oxygen consumption of rat liver mitochondria because of the inability to cross the outer membrane. The involvement of this membrane as a permeability barrier is demonstrated by the results with exogenous ferrocytochrome c. ADM does not affect the basal rate of ferrocytochrome c oxidation, which, on the contrary, increases in Lonidamine (LND)-treated mitochondria. This difference lies in the capacity of LND to unmask the redox carriers in the inner membrane, i.e. cytochrome c:oxygen oxidoreductase which is also a marker of the outer membrane permeabilization. Therefore, the enhancement of ADM's effect on mitochondrial respiration by LND must be ascribed to its permeabilizing effect on the outer mitochondrial membrane.
Insights
Adriamycin (ADM) cannot inhibit mitochondrial respiration due to outer membrane impermeability. Lonidamine (LND) enhances ADM
Area of Science:
- Mitochondrial Physiology and Pharmacology
- Cellular Respiration and Drug Action
- Biochemistry of Drug Permeability
Background:
- Adriamycin (ADM) is an anticancer drug with known mitochondrial effects.
- The mitochondrial outer membrane acts as a barrier to drug entry.
- Understanding drug permeability is crucial for optimizing therapeutic efficacy.
Purpose of the Study:
- To investigate the role of the mitochondrial outer membrane as a permeability barrier for Adriamycin (ADM).
- To elucidate the mechanism by which Lonidamine (LND) affects ADM's interaction with mitochondria.
- To determine if LND can enhance ADM's inhibitory effects on mitochondrial respiration.
Main Methods:
- Measurement of oxygen consumption in isolated rat liver mitochondria.
- Assessment of exogenous ferrocytochrome c oxidation rates.
- Evaluation of Adriamycin (ADM) and Lonidamine (LND) effects on mitochondrial respiration.
Main Results:
- Low concentrations of Adriamycin (ADM) did not inhibit mitochondrial oxygen consumption.
- Lonidamine (LND) treatment increased the oxidation of exogenous ferrocytochrome c, indicating outer membrane permeabilization.
- LND enhanced the inhibitory effect of ADM on mitochondrial respiration.
Conclusions:
- The mitochondrial outer membrane restricts Adriamycin (ADM) entry and its inhibitory action on respiration.
- Lonidamine (LND) acts as a permeabilizing agent for the outer mitochondrial membrane.
- The enhancement of ADM's effect by LND is attributed to LND-induced outer membrane permeabilization.