Mitophagy in Parkinson's Disease: From Pathogenesis to Treatment

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease. The pathogenesis of PD is complicated and remains obscure, but growing evidence suggests the involvement of mitochondrial and lysosomal dysfunction. Mitophagy, the process of removing damaged mitochondria, is compromised in PD patients and models, and was found to be associated with accelerated neurodegeneration. Several PD-related proteins are known to participate in the regulation of mitophagy, including PINK1 and Parkin. In addition, mutations in several PD-related genes are known to cause mitochondrial defects and neurotoxicity by disturbing mitophagy, indicating that mitophagy is a critical component of PD pathogenesis. Therefore, it is crucial to understand how these genes are involved in mitochondrial quality control or mitophagy regulation in the study of PD pathogenesis and the development of novel treatment strategies. In this review, we will discuss the critical roles of mitophagy in PD pathogenesis, highlighting the potential therapeutic implications of mitophagy regulation.

Keywords: PINK1; Parkin; Parkinson’s disease; mitophagy; treatment.

Figure 1

Mitophagy pathways. Mitophagy can be divided into Parkin-dependent or independent pathways. Under normal conditions, PINK1 localizes to mitochondria and is translocated to the mitochondrial inner membrane (MIM), where it is cleaved and subsequently degraded by an N-end rule pathway. However, when mitochondria become depolarized, PINK1 accumulates at the outer mitochondrial membrane (OMM) and recruits Parkin. Activated Parkin leads to the ubiquitination of substrates and the recruitment of autophagy receptors to initiate mitophagy. In addition, Parkin-independent mitophagy includes receptor-mediated and ubiquitin ligase-mediated mitophagy. BNIP3, BCL2/adenovirus E1B 19 kDa interacting protein 3; FUNDC1, FUN14 domain-containing protein 1; NDP52, nuclear dot protein 52 kDa; NIX, BCL2/adenovirus E1B 19 kDa interacting protein 3 like; OPTN, optineurin; Ub, ubiquitin.

Figure 2

PD-related proteins participate in mitophagy. PINK1 accumulates at the outer mitochondrial membrane (OMM) and recruits Parkin to initiate mitophagy. α-syn interacts with Miro and upregulates Miro protein levels, leading to excessive, abnormal Miro accumulation on the mitochondrial surface and delayed mitophagy. Mitochondrial localized α-syn also promotes cardiolipin exposure on OMM; the latter further recruited LC3 to mitochondria and induced mitophagy. LRRK2 interacts with RAB10, which binds OPTN to induce mitophagy. LRRK2 interacted with Miro and contributed to its removal via mitophagy. NDP52, nuclear dot protein 52 kDa; OPTN, optineurin; Ub, ubiquitin.

Figure 3

The PINK1–Parkin–Ub feedforward loop. PINK1, Parkin, and Ub form a feedforward mechanism of mitophagy. Regulation of this feedforward loop is a strategy for mitophagy modulation and PD treatment. PTEN-L dephosphorylate p-Ub and suppress mitophagy via blockage of the feedforward mechanism. USP30, USP35, and USP15 can counteract Parkin activity and regulate mitophagy negatively, while USP8 regulate Parkin and mitophagy positively. PTEN-L, phosphate and tension homology deleted on chromsome ten-long; Ub, ubiquitin; USP, ubiquitin specific protease.