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The mitochondrial membrane permeability transition induced by inorganic phosphate or inorganic arsenate. A
C Bravo1, E Chávez, J S Rodríguez
1Departamento de Bioquímica, Instituto Nacional de Cardiología, México D.F., Mexico.
Abstract:
The membrane permeability transition (MPT) induced by Ca2+ and Pi or Asi was studied in rat kidney mitochondria. Membrane potential, Ca2+ transport and swelling were used to monitor the MPT. Asi promoted a faster and more extensive collapse of membrane potential, Ca2+ release and swelling than Pi. The MPT induced by Pi was fully blocked by Mg(2+)+ADP, spermine+ADP, Mg(2+)+ cyclosporin A (CSA), and ADP+CSA. In contrast, the MPT induced by Asi was only prevented, although not completely, by CSA+Mg2+ or ADP+CSA. Asi, but not Pi, was able to cause collapse of membrane potential in the presence of Sr2+. Carboxyatractyloside (CAT) produced collapse of membrane potential at a lower concentration in the presence of Asi+Ca(2+)+ADP than with Pi+Ca(2+)+ADP. The addition of Pi+Ca2+ to [14C]-ADP loaded mitochondria brought about a greater ADP release than Asi+Ca2+. The ADP release was CAT-sensitive with Pi but it was only partially blocked by Asi. The diminution of external pH did not inhibit the MPT induced by Pi or Asi. The results of this study suggest that the adenine nucleotide translocase does not have an essential role in the MPT induced by Asi+Ca2+.
Insights
Arsenite (Asi) induces mitochondrial membrane permeability transition (MPT) more rapidly than phosphate (Pi). Unlike Pi-induced MPT, Asi-induced MPT is not fully inhibited by common blockers, suggesting a different mechanism.
Area of Science:
- Mitochondrial physiology
- Biochemistry
- Cellular toxicology
Background:
- Mitochondrial membrane permeability transition (MPT) is a critical event in cell death.
- Calcium (Ca2+) and inorganic phosphate (Pi) are known inducers of MPT.
- The role of other agents, like arsenite (Asi), in MPT induction requires further elucidation.
Purpose of the Study:
- To compare the effects of arsenite (Asi) and inorganic phosphate (Pi) on MPT induction in rat kidney mitochondria.
- To investigate the mechanisms underlying Asi-induced MPT and its potential differences from Pi-induced MPT.
Main Methods:
- Monitoring MPT using membrane potential, Ca2+ transport, and swelling assays in isolated rat kidney mitochondria.
- Testing the inhibitory effects of various agents including Mg2+, ADP, cyclosporin A (CSA), and carboxyatractyloside (CAT).
- Evaluating MPT induction under different conditions, including the presence of Sr2+ and varying external pH.
Main Results:
- Asi induced a faster and more pronounced collapse of mitochondrial membrane potential, Ca2+ release, and swelling compared to Pi.
- Pi-induced MPT was fully inhibited by Mg2++ADP, spermine+ADP, Mg2++CSA, and ADP+CSA.
- Asi-induced MPT was only partially prevented by CSA+Mg2+ or ADP+CSA, and Asi induced membrane potential collapse in the presence of Sr2+, unlike Pi.
- Carboxyatractyloside (CAT) induced membrane potential collapse at lower concentrations with Asi+Ca2++ADP than with Pi+Ca2++ADP, and ADP release was less sensitive to Asi than Pi.
Conclusions:
- Arsenite (Asi) induces mitochondrial membrane permeability transition (MPT) through a mechanism distinct from that of inorganic phosphate (Pi).
- The adenine nucleotide translocase may not play an essential role in Asi-induced MPT.
- These findings contribute to understanding the differential regulation of mitochondrial permeability transition by various chemical agents.