The evidence that a component of the MPT pore binds to proteins associated with the cytoskeleton supports the proposal that induction of the mitochondrial permeability transition (MPT) alters the cytoskeleton and thereby causes cell death. Exploration of this connection began with work on the toxicity of aluminum, specifically the effect of aluminum on tau, a microtubule associated protein
Aluminum binds to phosphate groups in the cell, interfering with the function of proteins that require phosphate groups for their activity, including microtubule-associated proteins (MAPs) such as tau. Reduced function of MAPs leads to instability in the microtubule cytoskeleton, which can interfere with intracellular trafficking, localization of organelles and plasma membrane function. Experiments described here show that exposure to aluminum damages the cytoskeleton and leads to loss of integrity of the plasma membrane, resulting in cell death.
Further experiments associate induction of the mitochondrial permeability transition (MPT) with subsequent alterations in the cytoskeleton. The work described here characterizes the cytoskeletal. alterations and connects them to induction of the MPT by using treatments that modulate the conformation of the MPT pore. Previous work in this lab has demonstrated that induction of the MPT kills cells by a mechanism that does not depend on either a decrease in intracellular ATP or loss of mitochondrial membrane potential. Depletion of intracellular ATP disassembles the cytoskeleton, since ATP is crucial for maintaining this structure, but not to the same degree as induction of the MPT. Treatment of L929 fibroblasts with cyclosporin A to stabilize the pore in the closed conformation leads to the appearance of stress fibers not seen in untreated cells or cells treated with another calcineurin inhibitor (cypermethrin). Therefore, the MPT pore is connected to the cytoskeleton in such a way that pore elements affect the organization of the cytoskeleton.
