Parkinson's disease (PD) is a debilitating neurodegenerative disease affecting more than 1% of the population aged >65 years (Mehta et al., ). PD is caused by progressive loss of substantia nigra dopaminergic neurons (SN-DA) and the motor symptoms of PD such as tremor, bradykinesia and rigidity typically begin to manifest when about 60% of SN-DA are degenerated (Dauer and Przedborski, ). Although the mechanism underlying PD-linked neurodegeneration remains elusive, growing evidence suggests mitochondrial dysfunction in the pathogenesis of sporadic and familial PD (Schapira, ). Consistently, several genes which have been associated with PD are known to cause mitochondrial dysfunction.
Among the PD-linked genes, loss-of-function mutations in PINK1 (PARK6; MIM# 608309) and Parkin (PARK2; MIM# 602544) are the most frequent cause of autosomal recessive early-onset PD (Klein and Westenberger, ). Functionally, PINK1 and Parkin play a crucial role in maintaining healthy mitochondria by regulating biogenesis, morphology, trafficking, and degradation (Scarffe et al., ), and recent advances greatly increased our understanding on their role in the autophagy-dependent selective degradation of dysfunctional mitochondria, termed mitophagy (reviewed in Youle and Narendra, ; Nguyen et al., ; Figure 1); Depolarization of mitochondria due to damage or aging stabilizes PINK1 on the outer mitochondrial membrane (OMM), which subsequently recruits Parkin to the dysfunctional mitochondria (Narendra et al., ). Then, Parkin, activated by PINK1-mediated phosphorylation (Narendra et al., ; Shiba-Fukushima et al., ), facilitates mitophagy by ubiquitinating OMM proteins to which the autophagosome receptor, microtubule-associated protein 1 light chain 3 (LC3), binds with help of polyubiquitin-binding adaptors (Youle and Narendra, ). Therefore, it is widely accepted, although in vivo evidence is still lacking due to the technical inability to monitor this process, that loss of PINK1 or Parkin induces impairment in mitophagy and accumulation of dysfunctional mitochondria, leading to nigrostriatal neurodegeneration, and PD (Scarffe et al., ). Intriguingly, several studies reported Parkin inactivation by structural modification such as S-nitrosylation (Chung et al., ), phosphorylation (Ko et al., ), and dopamine (LaVoie et al., ) in sporadic PD brains, suggesting the broader involvement of Parkin and impaired mitophagy in the pathogenesis of PD. In addition to the Parkin/PINK1-mediated pathway, several molecules including Fun14 domain-containing protein 1 (FUNDC1; Liu et al., ), FK506 binding protein 8 (FKBP8; Bhujabal et al., ), PINK1 (Lazarou et al., ), Autophagy and beclin 1 regulator 1 (AMBRA1; Strappazzon et al., ), and Gp78 (Fu et al., ) have been found to mediate mitophagy in a Parkin-independent manner.
Figure 1
The penetrance rate of Parkin-mediated PD is almost 100% (Schulte and Gasser, ), but recently we identified an asymptomatic homozygous Parkin mutation carrier (MC) who, despite the complete loss of Parkin, has not developed PD in her seventies (Koentjoro et al., ), suggesting the existence of a protective mechanism against Parkin deficiency. MC-derived fibroblasts showed sound mitochondrial function as shown by normal mitochondrial membrane potential and ATP production with well-preserved mitochondrial respiration, and intact mitophagy, indicating the presence of a Parkin-independent mitophagy (Koentjoro et al., ). As the molecular mechanism, the mitochondrial autophagy receptor Nip3-like protein X [Nix; also known as BCL2/adenovirus E1B 19 kDa interacting protein 3-like (BNIP3L)] was found to be responsible for maintaining mitochondrial quality by mediating mitophagy.
Nix, originally identified as a proapoptotic protein, has been known in association with mitophagy occurring in the development of reticulocytes (Ney, ). Although, a large part of the mechanism underlying Nix-mediate mitophagy such as recognition of dysfunctional mitochondria remains unknown, Nix mediates the isolation of mitochondria into autophagosomes through forming a protein complex with LC3/gamma-aminobutyric acid receptor-associated protein (GABARAP; Novak et al., ; Figure 1). Ras homolog enriched in brain protein (Rheb) has been shown to facilitate this process by promoting the interaction between Nix and LC3/GABARAP (Melser et al., ). In the presence of PINK1/Parkin-mediated mitophagy, Nix seems to function downstream of Parkin as a substrate; Nix, ubiquitinated by Parkin, binds to LC3/GABARAP through interaction with neighbor of BRCA1 (NBR1; Gao et al., ).
Contrary to the causative role of impaired mitophagy in PINK1/Parkin-related PD, the observation in MC on the ability of Nix to independently mediate mitophagy and thereby maintain normal mitochondrial function suggests that increased levels of Nix may compensate for the loss of PINK1/Parkin-mediated mitophagy in PD. Indeed, overexpression of Nix restored the cellular ability to activate mitophagy without triggering an aberrant increase in mitochondrial degradation or apoptosis, and improved mitochondrial energy production in cell lines derived from PINK1/Parkin-related PD patients (Koentjoro et al., ). Furthermore, induction of Nix expression using phorbol 12-myristate 13-acetate elicited a similar effect of restoring mitophagy, demonstrating the usefulness of Nix as a therapeutic target in drug development and human application. Taken together, these findings strongly support that Nix is responsible for prevention of PD as well as PD-associated neurodegeneration in MC, and has a therapeutic potential for PINK1/Parkin-related PD as a neuroprotective treatment.
Although, our study suggests Nix-mediated pathway as an innovative avenue to treat PD, there are key questions to be answered for clinical application of Nix. Particularly, the protective effect of Nix in animal models and the mechanisms underlying Nix induction and Nix-mediated mitophagy need to be urgently clarified. Also, knowledge on the expression of Nix in SN-DA of PD patients and animal models is of great interest. In addition, further evidence on the involvement of mitophagy in PD pathogenesis, especially sporadic cases, would also be beneficial.
Mitochondrial dysfunction has been shown to underlie neurodegeneration associated with PD. As the cause of mitochondrial dysfunction, defective mitophagy by loss of PINK1/Parkin has been shown in early-onset familial PD while evidence is growing in sporadic PD, broadening applicability of our approach to restore mitophagy as a treatment for PD. In this context, the newly identified compensatory role of Nix in mediating PINK1/Parkin-independent mitophagy provides a promising therapeutic target to treat mitochondrial dysfunction, which may lead to the development of a neuroprotective therapy for PD.
Statements
Author contributions
All authors listed, have made substantial, direct, and intellectual contribution to the work, and approved it for publication.
Acknowledgments
JP, BK, and CS are recipients of a Parkinson's NSW seed grant. CS received grant funding from the University of Sydney for this project. CS has been awarded project grants from the National Health and Medical Research Council (NHMRC) and is a NHMRC Practitioner Fellow (APP1008433).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
Parkinson's disease, Parkin, PINK1, mitophagy, nix
Citation
Park J-S, Koentjoro B and Sue CM (2017) Commentary: Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson's disease. Front. Mol. Neurosci. 10:297. doi: 10.3389/fnmol.2017.00297
Received
25 May 2017
Accepted
05 September 2017
Published
19 September 2017
Volume
10 - 2017
Edited by
Jean-Marc Taymans, Institut National de la Santé et de la Recherche Médicale, France
Reviewed by
Susan Fox, University Health Network, Canada; Chris Van Den Haute, KU Leuven, Belgium; Yunjong Lee, Sungkyunkwan University, South Korea
Updates
Copyright
© 2017 Park, Koentjoro and Sue.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jin-Sung Park jin.park@sydney.edu.au
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