Precise control of mitophagy through ubiquitin proteasome system and deubiquitin proteases and their dysfunction in Parkinson's disease

Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative diseases in the elderly population and is caused by the loss of dopaminergic neurons. PD has been predominantly attributed to mitochondrial dysfunction. The structural alteration of α-synuclein triggers toxic oligomer formation in the neurons, which greatly contributes to PD. In this article, we discuss the role of several familial PD-related proteins, such as α-synuclein, DJ-1, LRRK2, PINK1, and parkin in mitophagy, which entails a selective degradation of mitochondria via autophagy. Defective changes in mitochondrial dynamics and their biochemical and functional interaction induce the formation of toxic α-synucleincontaining protein aggregates in PD. In addition, these gene products play an essential role in ubiquitin proteasome system (UPS)-mediated proteolysis as well as mitophagy. Interestingly, a few deubiquitinating enzymes (DUBs) additionally modulate these two pathways negatively or positively. Based on these findings, we summarize the close relationship between several DUBs and the precise modulation of mitophagy. For example, the USP8, USP10, and USP15, among many DUBs are reported to specifically regulate the K48-or K63-linked de-ubiquitination reactions of several target proteins associated with the mitophagic process, in turn upregulating the mitophagy and protecting neuronal cells from α-synuclein-derived toxicity. In contrast, USP30 inhibits mitophagy by opposing parkin-mediated ubiquitination of target proteins. Furthermore, the association between these changes and PD pathogenesis will be discussed. Taken together, although the functional roles of several PD-related genes have yet to be fully understood, they are substantially associated with mitochondrial quality control as well as UPS. Therefore, a better understanding of their relationship provides valuable therapeutic clues for appropriate management strategies.

Inhibition of mitoNEET induces Pink1-Parkin-mediated mitophagy

“…These results demonstrated that NL-1 or mitoNEET shRNA may attenuate CCCP-induced mitochondrial ROS production through the upregulation of the expression of antioxidant defense genes with enhanced mitophagy. Furthermore, PGC-1α, as a major regulator of mitochondrial biogenesis, maintains a network of healthy mitochondria by balancing the generation of new organelles and the removal of damaged mitochondria ( 8 , 22 ). We did another experiment to demonstrate that mitoNEET inhibition induces the activation of mitochondrial biogenesis via the increase of PGC-1α and the activation of mitophagy via increase of Drp-1 (a fission protein) and decrease of mitofusin 2 (Mfn2; a fusion protein) in the presence with CCCP by western blot analysis.…”

“…4 ). Particularly, as PGC-1α is a major regulator of mitochondrial biogenesis, the balance of elevated PGC-1α and mitophagy assures maintenance of the mitochondrial contents ( 8 , 22 ). CCCP-induced ROS, disequilibrium of mitochondrial homeostasis cause deterioration of mitochondrial function and cell death ( 22 , 23 ).…”

“…The kinases promote each other and stimulate a downstream regulation of autophagy ( 6 , 7 ). Consequently, Pink1–Parkin-mediated mitophagy, receptor-mediated mitophagy, or adaptor protein-mediated mitophagy is triggered ( 8 ). The polyubiquitination of various mitochondrial outer membrane proteins by Parkin induces the recognition of several adaptor molecules and microtubule‐associated protein 1 light chain 3 (LC3) and the recruitment of autophagic machinery ( 6 , 8 , 9 ).…”

“…Consequently, Pink1–Parkin-mediated mitophagy, receptor-mediated mitophagy, or adaptor protein-mediated mitophagy is triggered ( 8 ). The polyubiquitination of various mitochondrial outer membrane proteins by Parkin induces the recognition of several adaptor molecules and microtubule‐associated protein 1 light chain 3 (LC3) and the recruitment of autophagic machinery ( 6 , 8 , 9 ). The mitophagy-enhancing process facilitates the elimination of damaged mitochondria and is the basis for developing therapeutic strategies for several diseases.…”

Miro proteins and their role in mitochondrial transfer in cancer and beyond

“…These targets comprise, for example, a group of import receptors and ion channels such as TOM20, VDAC1 or VDAC3, and Mfn1 and Mfn2 proteins involved in the process of fusion and fission to block the fusion of defective mitochondria and Miro proteins ( Geisler et al, 2010 ; Wang X. et al, 2011 ; Sun et al, 2012 ; Bingol et al, 2014 ; Birsa et al, 2014 ; Choubey et al, 2014 ). Parkin further facilitates K48 and K63 ubiquitination of substrates and recruits the autophagy machinery and complexes of lysosomal degradation ( Olzmann et al, 2007 ; Moore et al, 2008 ; Richard et al, 2020 ; Park et al, 2021 ). Degradation of Miro by Parkin is a prerequisite for the arrest of mitochondrial movement, so that clearance of mitochondria can properly proceed ( Wang X. et al, 2011 ; Birsa et al, 2014 ).…”