Mitochondrial deenergization and the subsequent formation of the permeability transition are critical to hypoxic cell killing

John Gaetano Pastorino, Thomas Jefferson University

Abstract

The cellular injury produced by hypoxia is a multistage process beginning with an inhibition of the respiratory chain and ending with a loss in the integrity of the plasma membrane. Prevention of electron transport in the respiratory chain inhibits proton pumping by the respiratory complexes with an eventual loss of the mitochondrial proton electrochemical potential ($\Delta\mu$H+) and ATP depletion. Loss of the $\Delta\mu$H+ is more critical to cell killing than ATP depletion. Evidence for this comes from the observation that oligomycin, an ATP synthase inhibitor, depletes ATP at the same rate and to the same extent as when respiration is inhibited by rotenone, cyanide or hypoxia yet oligomycin does not collapse the $\Delta\mu$H+ or cause the cell killing seen under the latter conditions. Additionally, by inhibiting the hydrolysis of ATP by the ATP synthase, oligomycin prevents the ATP produced through the glycolysis of fructose from maintaining the $\Delta\mu$H+ and thus protecting against the toxicity of cyanide and hypoxia. Collapse of the $\Delta\mu$H+ in turn promotes the formation of the mitochondrial permeability transition(MPT), a critical event in cell killing. Support for this comes from the ability of cyclosporin A (CyA) to inhibit MPT induction and cell killing promoted by respiratory inhibition in isolated liver mitochondria and hepatocytes. Furthermore, CyA does not prevent mitochondrial deenergization, demonstrating that MPT induction takes place subsequent to and as a consequence of $\Delta\mu$H+ collapse. L-Carnitine exhibited properties similar to CyA, suggesting the involvement of long chain acyl CoAs in MPT induction in intact cells during respiratory inhibition. The importance of the matrix calcium concentration in MPT induction is underscored by the prevention of cell killing and MPT induction by the intracellular calcium chelator BAPTA-AM. Also demonstrated is the possible involvement of a peripheral mitochondrial benzodiazepine receptor complex(mBzR) in MPT formation and cell death. The mBzR ligands diazepam and PK11195 potentiated both MPT formation and the killing of hepatocytes by respiratory inhibition with both of these effects being inhibited by CyA.

Subject Area

Cellular biology

Recommended Citation

Pastorino, John Gaetano, "Mitochondrial deenergization and the subsequent formation of the permeability transition are critical to hypoxic cell killing" (1994). ETD Collection for Thomas Jefferson University. AAI9426844.
https://jdc.jefferson.edu/dissertations/AAI9426844

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