Mitochondrial pore dysfunction, a novel mechanism for age-related disease.

摘要

Cells rely on mitochondria to harness energy, perform metabolic reactions, and regulate cell death. Thus, mitochondrial dysfunction can potentially contribute to disease through multiple pathways. As the primary consumer of oxygen, mitochondria could generate harmful oxidative stress; as the primary producer of ATP, mitochondria could starve the cell for energy; as a controller of cell death, mitochondria could activate apoptosis. Mitochondria accumulate DNA mutations with age, and these mutations have been hypothesized to compromise mitochondrial function and contribute to age-related diseases.; We are studying mice that accumulate mitochondrial DNA mutations because of a proofreading-deficient mitochondrial DNA polymerase. These transgenic mice express the polymerase in the heart, and develop heart disease. Disease was not associated with oxidative stress. Oxidative protein adducts were not increased, and antioxidant defense systems were not activated. Neither was there a decrease in energy production.; Instead, disease correlated with changes in apoptotic signaling. Opening of the mitochondrial permeability transition pore can activate cell death and inhibition of the pore is protective. The pore was found to be inhibited in mice, approximately coincident with disease onset. Data were consistent with Bcl-2 mediated inhibition.; Cyclosporin A is an inhibitor of the pore and cyclosporin A-treatment was able to protect mice from disease. Thus in isolated mitochondria the pore is dysfunctional, and inhibition of the pore in mice prevents disease.