Many DUBs regulate mitophagy in a positive or negative manner. In healthy mitochondria, PINK1 is constitutively imported into the mitochondria for processing and release into the cytosolic area, followed by rapid degradation. However, when the mitochondrial membrane potential (ΔΨm) dissipates, PINK1 is stabilized on the OMM and forms a large complex on the OMM surface where it recruits parkin to the damaged mitochondria. The accumulated PINK1 phosphorylates parkin and attaches ubiquitin chains to several mitochondrial substrates, such as translocase of the outer membrane 20 (Tom20), voltage-dependent anion-selective channel 1 (VDAC1), and mitofusin-2 (MFN2). Such ubiquitinated proteins may act as adaptors for sequestosome-1 (SQSTM1/p62) and promote the translocation of defective mitochondria to the autophagosome followed by sequential steps of mitophagy. Multiple DUBs regulate mitophagy in a positive/negative manner. For example, USP8 and USP13 promote mitophagy by directly detaching ubiquitin from parkin, whereas USP15, USP30, USP33, and USP35 inhibit parkin-mediated ubiquitination of OMM proteins. Accordingly, these DUBs promote or suppress mitophagy during the removal of ubiquitin from the parkin. USP14 negatively regulates proteasome activity, and also acts as a negative regulator of mitophagy.
