Cited by 502Autophagy in Disease and TherapyParkinson's Disease Mechanisms and TreatmentsUbiquitin and proteasome pathways

Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin

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Ashrafi, Ghazaleh, Schlehe, Julia S., LaVoie, Matthew J., Schwarz, Thomas L.·2014·Journal of Cell Biology

Abstract

To minimize oxidative damage to the cell, malfunctioning mitochondria need to be removed by mitophagy. In neuronal axons, mitochondrial damage may occur in distal regions, far from the soma where most lysosomal degradation is thought to occur. In this paper, we report that PINK1 and Parkin, two Parkinson’s disease–associated proteins, mediate local mitophagy of dysfunctional mitochondria in neuronal axons. To reduce cytotoxicity and mimic physiological levels of mitochondrial damage, we selectively damaged a subset of mitochondria in hippocampal axons. Parkin was rapidly recruited to damaged mitochondria in axons followed by formation of LC3-positive autophagosomes and LAMP1-positive lysosomes. In PINK1−/− axons, damaged mitochondria did not accumulate Parkin and failed to be engulfed in autophagosomes. Similarly, initiation of mitophagy was blocked in Parkin−/− axons. Our findings demonstrate that the PINK1–Parkin-mediated pathway is required for local mitophagy in distal axons in response to focal damage. Local mitophagy likely provides rapid neuroprotection against oxidative stress without a requirement for retrograde transport to the soma.

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  • Axonal autophagy is dependent on specialized enzymatic apparatuses, including the PINK1-PRKN complex for localized mitophagy, KIF1A/UNC-104 for autophagosome formation at the synapse, and the HTT-HAP1 complex and MAPK8IP1/JIP1 for retrograde transport of autophagosomes.

    “Axonal autophagy is dependent on specialized enzymatic apparatuses, including the PINK1-PRKN complex for localized mitophagy [24], KIF1A/UNC-104 for autophagosome formation at the synapse [22,25], and the HTT-HAP1 complex and MAPK8IP1/JIP1 for retrograde transport of autophagosomes [23,26].”

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Authors
Ashrafi, G., Schlehe, J. S., LaVoie, M. J., & Schwarz, T. L.
Affiliations
  • Boston Children's Hospital (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Schwarz, Thomas L.
Venue
Journal of Cell Biology
Published
2014-08-25
Volume
206
Issue
5
Pages
655-670
ISSN
  • 0021-9525 (ISSN-L)
  • 1540-8140
OpenAlex
W1992264711
Cited by
502
References
65
Citations by year
2026: 18 · 2025: 22 · 2024: 39 · 2023: 25 · 2022: 39 · 2021: 53 · 2020: 53 · 2019: 51 · 2018: 49 · 2017: 49 · 2016: 51 · 2015: 46 · 2014: 7
FWCI
38.33
Type
journal article
Language
en
Open access
Licence
cc-by-nc-sa
Locations
  • The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders
  • National Institute of General Medical Sciences (GM069808, R01GM069808)
  • National Institute of Neurological Disorders and Stroke (R21NS069949, R01NS065013, NS065013, NS069949)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-01866, P30HD018655)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords
mitophagy, PINK1, Parkin, axons, mitochondrial damage, Parkinson's disease, autophagosomes, lysosomes, oxidative stress, neuroprotection, hippocampal neurons, retrograde transport, mitochondrial quality control
MeSH terms
PTEN-Induced Putative Kinase, Animals, Antimycin A, Autophagy, Axons, Cells, Cultured, Female, Lysosomes, Mice, Inbred C57BL, Microtubule-Associated Proteins, Mitochondria, Phagosomes, Protein Kinases, Veratridine, Rats, Sprague-Dawley, Mice, Knockout, Rats, Long-Evans, Protein Transport, Ubiquitin-Protein Ligases, Mice, Rats, Membrane Potential, Mitochondrial, Mice, 129 Strain, Mitophagy

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