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Parkinson’s Disease: A Disorder of Axonal Mitophagy? Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin. J Cell Biol Sep 1;206:655-670. doi: 10.1083/jcb.201401070. Epub 2014 Aug 25.
Neurons, perhaps more than many other cell types, depend on mitochondria to maintain structure and function, but their postmitotic character and exceptional cellular architecture pose tremendous challenges. Mitochondrial homeostasis is preserved by the effective clearance of damaged mitochondria through mitophagy, a selective subtype of the autophagy–lysosomal pathway. A large proportion of neuronal mitochondria reside in distal dendritic and axonal processes, where the local demand for adenosine triphosphate production and calcium buffering is high, but lysosomes, the organelles necessary for degradation of dysfunctional or superfluous mitochondria, are thought to be scarce. The latter has led to the widespread notion that mitochondria have to be delivered back to the soma through retrograde transportation to be degraded, although this process is clearly time and energy intensive, would not allow for rapid clearance of damaged mitochondria, and thus might expose axons to significant levels of oxidative stress. Mitochondrial dysfunction, oxidative stress, and defective mitophagy have been implicated in the pathogenesis of Parkinson’s disease (PD) through several lines of evidence. One such line of evidence stems from the sequential involvement of the familial PD associated proteins PINK1 (PARK6), a serine/threonine kinase, and Parkin (PARK2), an E3 ubiquitin ligase, in the initiation and regulation of mitophagy. PINK1 acts as a sensor for mitochondrial damage and accumulates on the outer mitochondrial membrane on loss of mitochondrial membrane potential. This leads to the subsequent recruitment of Parkin to the mitochondrial membrane, where it initiates the autophagic machinery to engulf and degrade dysfunctional mitochondria. In an elegant study, recently published in the Journal of Cell Biology, Ashrafi and colleagues set out to investigate whether local mitophagy might occur in regions far from the soma, such as in distal axons, and thus might provide a more rapid and dynamic means to maintain mitochondrial homeostasis locally.1 To study mitophagy in the axonal compartment and to induce mitochondrial damage at a level that might approximate the extent of mitochondrial dysfunction normally found in neurons, the authors employed a novel methodological approach by combining time-lapse confocal microscopy in cultured living, intact neurons with the application of a genetically encoded mitochondriatargeted photosensitizer, mito-KillerRed, to induce mitochondrial damage in a spatiotemporally controlled manner.
Using this approach or pharmacological depolarization of axonal mitochondria in specific cell culture chambers, socalled microfluidic devices, they were able to show that Parkin is rapidly recruited to damaged axonal mitochondria followed by the local formation and engulfment by autophagic vesicles, so-called autophagosomes. These fuse with local, mobile lysosomes, leading to an effective clearance of mitochondrial cargo. Having studied and established local axonal mitophagy in an unprecedented way, the authors next asked whether this process required the presence and function of PINK1 and Parkin, respectively, a question that had been previously addressed in immortalized non-neuronal cell lines but has remained controversial for neurons. Using primary neuronal cultures derived from PINK1 mutant rats and Parkin knockout mice, they found that both proteins are indeed required for the effective removal of axonal mitochondria through mitophagy, therefore highlighting the importance of the PINK1/Parkin–mediated pathway for neuronal mitophagy. The seminal findings by Ashrafi et al. are of great importance because they help to clarify previous controversies in the field and establish PINK1- and Parkin-mediated local axonal mitophagy as a novel pathway that abrogates the need for retrograde organelle transportation and ensures a rapid and local control of dysfunctional mitochondria in axons. The contribution of defective axonal mitophagy to mitochondrial dysfunction and axonal degeneration in PD and other neurodegenerative diseases will have to explored in future studies. Darius Ebrahimi-Fakhari, MD,1,2* Lara Wahlster, MD,1 and Mustafa Sahin, MD, PhD2 1 Division of Inherited Metabolic Diseases & Pediatric Neurology, Department of Pediatrics, Heidelberg University Hospital, RuprechtKarls University Heidelberg, Germany 2 Department of Neurology, Children’s Hospital Boston, Harvard Medical School, Boston, MA, USA
Reference 1.
Ashrafi G, Schlehe JS, LaVoie MJ, Schwarz TL. Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requirs PINK1 and Parkin. J Cell Biol 2014;206:655-670. doi:10.1083/jcb.201401070.
-----------------------------------------------------------------------------------------------------------------------------*E-mail:
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Funding agencies: Research by D.E.F. is supported by the Graduate Academy of the University of Heidelberg, the Young Investigator Award Program at Ruprecht-Karls-University Heidelberg Faculty of Medicine, the Daimler and Benz Foundation (Daimler und Benz Stiftung, Ladenburg, Germany) and the Reinhard-Frank Foundation (Reinhard-Frank-Stiftung, Hamburg, Germany). Research by L.W. is supported by the Graduate Academy of the University of Heidelberg. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 3 September 2014; Accepted: 11 September 2014 Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26047
Movement Disorders, Vol. 00, No. 00, 2014
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