Mitochondrial autophagy (mitophagy) is a specialized aspect of the overall, non-selective bulk macroautophagy, or autophagy pathway. Mitophagy allows for the removal of damaged mitochondria and for mitochondrial depletion, as required in certain cell states or in development. Removal of mitochondria proceeds via alternative routes. One involves the Pink1-Parkin duo responding to loss of mitochondrial membrane potential and mediated via ubiquitination events. Another route involves the mitophagy
receptors and responds to stresses such as hypoxia or facilitates mitochondria removal under normal physiological, developmental conditions. Mitophagy shares elements with bulk autophagy but also exhibits unique elements whose detailed molecular functions and their regulation are still to be determined. In all cases, damaged mitochondria are targeted to an autophagosome at a stage subsequent to its initiation. Largely, the upstream elements are not well known, although autophagy components such as Beclin1 or Ulk1, have been shown to be required for mitophagy. Mitochondrial stress also promotes the translocation of cardiolipin (CL), the signature phospholipid of the IMM, to the OMM; the externalized CL will trigger mitophagy or apoptosis depending on the magnitude of the injury. ( click to see the normal mitochondrial autophagy pathway).
Pink1-Parkin is the main route of mitochondria quality control (QC) involving the nuclear-encoded mitochondrial serine/threonine kinase Pink1 and downstream of it, the cytosolic E3 ubiquitin ligase Parkin (Park2). The kinase activity promotes recruitment of Parkin to the damaged mitochondria and is necessary for its E3 ubiquitin ligase activity. Parkin ubiquitinates itself and substrates and the ubiquitin conjugates can be phosphorylated by Pink1 to further increase Parkin activity in a feed-forward loop. Ubiquitinated substrates can promote the recruitment of Ub-binding autophagy receptors/adapters such as S1stm1/p62 and optineurin. Other ubiquitinated substrates are targeted for proteosomal degradation; they include the mitofusins and Miro GTPase proteins involved in mitochondria fusion and transport, respectively. Miro is also a substrate for Pink1. Thus, Pink1 and Park2 also modulate mitochondria dynamics. Inhibition of fusion helps fragment mitochondria networks and isolate damaged mitochondria via fission; inhibition of transport prevents delivery of damaged mitochondria at nerve terminals where they are necessary for energy supply, while promoting a retrograde transport for degradation.
Inactivating mutations in the two proteins have been associated with Parkinson disease (PD), the familial form of this neurodegenerative condition ( click to link to the diagram page for PD pathway). Not only is the mitochondrial autophagy profoundly impaired through their inactivation, but other aspects of mitochondrial function are also affected. As mentioned above, the two proteins negatively control mitochondria dynamics, namely fusion and transport, thus circumventing the propagation and use of damaged organelles. Removal of these inhibitory effects abrogates the protective roles they exert. While an altered mitochondrial autophagy pathway can likely trigger a cell death response in all cell types, its effects on the more vulnerable dopaminergic neurons in the substantia nigra pars compacta (SNc) can likely trigger a heightened response. These neurons are selectively lost in PD. To see the ontology report for GViewer, annotations and download, click here...(less)