pISSN 1976-2283
eISSN 2005-1212

Download original image
Fig. 4. Mitophagy inhibits pathways of mitochondrial dysfunction and associated cell death and inflammation. Mitophagy restitutes physiological cell functioning by inhibiting mitochondrial-related cell death and/or injury arising either from the generation of reactive oxygen-species (ROS) or pro-inflammatory signals, or as a result of mitochondrial membrane permeability transition (MPT). During activation of the intrinsic apoptosis pathway, BH3-only protein members, including BAK and BAX, effect mitochondrial membrane permeabilisation (MOMP) and release of intermembrane space proteins, including cytochrome c which induces a downstream caspase cascade activation that leads to apoptosis. Alternatively, necrotic cell death may be initiated by cyclophilin D-dependent initiation of MPT pore. Once opened, MPT destroys the mitochondrial transmembrane potential (Δψm), thereby abrogating oxidative phosphorylation and exacerbating ROS generation. Excessive ROS formation can activate the NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome. Uncoupling of oxidative phosphorylation can also trigger MPT, during which mtDNA may undergo cytoplasmic translocation, leading to nuclear factor-kappa B (NF-κB) and interferon regulatory factor-dependent inflammatory pathway activation. Importantly, excess intra-mitochondrial ROS is able to mutate mitochondrial DNA (mtDNA), leading to premature aging and mitochondrial inefficiency post-replication (this in turn exacerbates ROS generation through impaired oxidative phosphorylation).
Gut Liver 2012;6:149~171 https://doi.org/10.5009/gnl.2012.6.2.149
© Gut and Liver