Adenine Nucleotide Translocase, Mitochondrial Stress, and Degenerative Cell Death
Figure 2
Proposed models for the pathogenic mechanisms of human diseases induced by dominant missense Ant1 mutations. These models predict that the mutant proteins (1) are defective in targeting onto the mitochondrial inner membrane; (2) are defective in nucleotide transport which sequentially causes ATP overaccumulation in the matrix, electron transport chain stalling, membrane hyperpolarization, increased ROS production, and oxidative damage; (3) are engaged in the futile ATPcytosol/ATPmatrix exchange which leads to matrix nucleotide imbalance and mtDNA deletions; (4) reverse the ADPcytosol/ATPmatrix exchange under normal conditions which also leads to ATP overaccumulation in the matrix; and (5) cause proteostatic stress on the mitochondrial inner membrane.
