The Role of the Antioxidant Response in Mitochondrial Dysfunction in Degenerative Diseases: Cross-Talk between Antioxidant Defense, Autophagy, and Apoptosis

Figure 1

Mitochondrial homeostasis is dynamically maintained by the processes of mitochondrial biogenesis, mitochondrial fusion/fission, mitophagy, and apoptosis. The upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α), nuclear respiratory factor 1 (NRF1), and mitochondrial transcription factor A (TFAM) promotes mitochondrial biogenesis. In mammals, mitochondrial fusion is facilitated by mitofusin (MFN) 1 and 2 and OPA1 for the fusion of the outer and inner mitochondrial membranes, respectively. Mitochondrial fission involves dynamin-related protein 1 (DRP1) that interacts with fission protein 1 (FIS1), which compartmentalizes damaged mitochondrial components into daughter mitochondria for elimination via mitophagy. Decreased ATP levels and membrane potential () and increased ROS generation are features of damaged mitochondria. These dysfunctional mitochondria are detected by phosphatase and tensin homologue deleted on chromosome 10- (PTEN-) induced putative kinase 1 (PINK1) and recruits Parkin, which initiates mitophagy and the subsequent formation of the autophagosome to degrade targeted mitochondria. Damaged mitochondria can also induce apoptosis through the permeabilization of the mitochondrial membrane, leading to the release of cytochrome c that can activate caspase-mediated apoptosis, as well as the release of proapoptotic proteins such as apoptosis-inducing factor (AIF).