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Mitophagy of damaged mitochondria occurs locally in distal neuronal axons and requires PINK1 and Parkin
Open accessAbstract
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 [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].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [22]
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Cites
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BackgroundParkin is recruited selectively to impaired mitochondria and promotes their autophagy
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InfluentialChronic systemic pesticide exposure reproduces features of Parkinson's disease
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BackgroundOverhoff, M., Tellkamp, F., Heß, S., Tutas, J., Tolve, M., Faerfers, M., Ickert, L., Mohammadi, M., Bruyckere, E. D., Kallergi, E., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2022110963 · Cited by 52
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Yang, T.-H., Kang, E. Y., Lin, P., Yu, B. B.-C., Wang, J. H.-H., Chen, V., & Wang, N. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168626 · Cited by 59
“…axons recruits Parkin for mitophagy, a process absent in PINK1 -mutated neurons, demonstrating the role of PINK1/Parkin pathway in local mitophagy [197] Mice (Obesity) Metformin Reduced ER stress and p53 levels to restore Parkin-mediated mitophagy in hepatocytes [198] Rat (Glaucoma)…”
BackgroundAssessment of Autophagy in Neurons and Brain Tissue
Benito‐Cuesta, I., Díez, H., Ordóñez‐Gutiérrez, L., & Wandosell, F. G. (2017) · Cells · doi:10.3390/cells6030025 · Cited by 52
“Indeed, there is evidence that the axon plays an important role in constitutive autophagosome generation and transport [24,26], and that axonal transport is essential to clear damaged mitochondria [26] even though their autophagic degradation may occur locally [27].”
BackgroundParkin absence accelerates microtubule aging in dopaminergic neurons
Cartelli, D., Amadeo, A., Calogero, A. M., Casagrande, F., Gregorio, C. D., Gioria, M., Kuzumaki, N., Costa, I., Sassone, J., Ciammola, A., et al. (2017) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2017.09.010 · Cited by 50
Cheng, X., & Sheng, Z. (2020) · Developmental Neurobiology · doi:10.1002/dneu.22748 · Cited by 50
“This may suggest local degradation of stressed or aging mitochondria along the axon by active lysosomes (Ashrafi et al., 2014; FarfelBecker et al., 2019).”
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Autophagy and the endolysosomal system in presynaptic function
Andres‐Alonso, M., Kreutz, M. R., & Karpova, A. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03722-5 · Cited by 49
“Selective removal of these organelles by autophagy, a process termed mitophagy, has been shown to occur at distal axons [59] and mitochondria are commonly found in autophagosomes [60].”
BackgroundBiogenetic and morphofunctional heterogeneity of mitochondria: the case of synaptic mitochondria
Fedorovich, S. V., Waseem, T. V., & Puchkova, L. V. (2017) · Reviews in the Neurosciences · doi:10.1515/revneuro-2016-0077 · Cited by 52
“However, sometimes, mitochondria can be degraded locally in axons (Ashrafi et al., 2014) or even transported to surrounding astrocytes for disassembling (Davis et al.”
Multiple pathways for mitophagy: A neurodegenerative conundrum for Parkinson’s disease
Chu, C. T. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.04.004 · Cited by 50
“Studies focusing on primary neurons or neurons differentiated from induced pluripotent stem cells have yielded conflicting interpretations concerning activation of the PINK1-Parkin pathway, ranging from no increase over baseline in cortical, striatal or midbrain neurons to parkin recruitment to 16% of Killer reddepola…”
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“Recent studies implicate the Parkinson’s disease (PD)-related proteins PTEN-induced putative kinase (PINK1) and Parkin, an E3 ubiquitin ligase, as critical mediators of mitophagy in axons and presynaptic terminals of hippocampal neurons [13].”
BackgroundMetabolic Regulation of Mitochondrial Protein Biogenesis from a Neuronal Perspective
Hees, J. T., & Harbauer, A. B. (2022) · Biomolecules · doi:10.3390/biom12111595 · Cited by 53
Giovedı̀, S., Ravanelli, M. M., Parisi, B., Bettegazzi, B., & Guarnieri, F. C. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.602116 · Cited by 53
“Mitophagy can occur in both cell body and distal axons (Cai et al., 2012; Ashrafi et al., 2014; Evans and Holzbaur, 2020).”
BackgroundNeuronal Mitophagy: Friend or Foe?
Doxaki, C., & Palikaras, K. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.611938 · Cited by 48
“…further support the notion that mitophagy is differentially regulated across neuronal compartments, as it is previously demonstrated both in vitro and in vivo (Ashrafi et al., 2014; Devireddy et al., 2015; Mcwilliams et al., 2016; Sung et al., 2016; Puri et al., 2019; Zaninello et al., 2020).”
BackgroundImpaired Mitophagy in Neurons and Glial Cells during Aging and Age-Related Disorders
Sukhorukov, V. S., Воронков, Д. Н., Baranich, T. I., Mudzhiri, N. M., Magnaeva, A., & Illarioshkin, S. N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910251 · Cited by 50
Transporting mitochondria in neurons
Course, M. M., & Wang, X. (2016) · F1000Research · doi:10.12688/f1000research.7864.1 · Cited by 47
Novel insights into the clinical and molecular spectrum of congenital disorders of autophagy
Teinert, J., Behne, R., Wimmer, M., & Ebrahimi‐Fakhari, D. (2019) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.12084 · Cited by 48
“Local autophagic degradation of cargo in axons, including that of dysfunctional mitochondria, has been observed.(12,103) Thus it seems that autophagy is present in axons where it is essential for axonal homeostasis.”
BackgroundThe R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy
Almutawa, W., Smith, C., Sabouny, R., Smit, R. B., Zhao, T., Wong, R., Lee-Glover, L. P., Desrochers-Goyette, J., Ilamathi, H. S., Suchowersky, O., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.06.018 · Cited by 45
“Additionally, as fission is required for the autophagic removal of mitochondria [47], which has been reported to occur in axons [48,49], impaired peripheral mitochondrial fission could also inhibit”
BackgroundDecreasing pdzd8-mediated mito–ER contacts improves organismal fitness and mitigates Aβ 42 toxicity
Hewitt, V. L., Miller‐Fleming, L., Twyning, M. J., Andreazza, S., Mattedi, F., Prudent, J., Polleux, F., Vagnoni, A., & Whitworth, A. J. (2022) · Life Science Alliance · doi:10.26508/lsa.202201531 · Cited by 45
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“Damaged mitochondria can be halted by PINK1/Parkin-dependent Miro degradation and then displaced from theMTs, followed by local clearance byautophagy (33,34).”
BackgroundKleesattel, D., Crish, S. D., & Inman, D. M. (2015) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.15-17885 · Cited by 45
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“In cardiomyocytes, autophagy, especially mitochondrial autophagy, is an important adaptive stress response that can be rapidly upregulated after cardiac injury to clear damaged mitochondria before they cause further damage to the cell.(5) MicroRNAs (miRs) are a family of small, noncoding, regulatory RNAs composed of 1…”
BackgroundMorris, G., Walder, K. R., Berk, M., Marx, W., Walker, A. J., Maes, M. H. J., & Puri, B. K. (2020) · Molecular Biology Reports · doi:10.1007/s11033-020-05590-5 · Cited by 47
“The importance of stimulating mitophagy in the context of a therapeutic intervention aimed at ameliorating mitochondrial dysfunction and oxidative stress in patients with neuroprogressive conditions is difficult to overemphasise owing to accumulating evidence which associates increases in this specific form of autopha…”
BackgroundRegulation of neuronal bioenergetics as a therapeutic strategy in neurodegenerative diseases
Onyango, I. G., Bennett, J. P., & Stokin, G. B. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.303007 · Cited by 45
“It is also crucial for quality control as elimination of damaged mitochondria by mitophagy via the PINK1/parkin pathway (Narendra et al., 2008, 2010; Ashrafi et al., 2014; Pickrell and Youle, 2015) involves mitochondrial fission (Tanaka et al.”
BackgroundOrganization of the autophagy pathway in neurons
Sidibe, D. K., Vogel, M. C., & Maday, S. (2022) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2022.102554 · Cited by 39
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Mitochondria modulate programmed neuritic retraction
Баранов, В. С., Baranova, O. V., Yablonska, S., Suofu, Y., Vazquez, A. L., Kozai, T. D. Y., Cui, X. T., Ferrando, L. M., Larkin, T. M., Tyurina, Y. Y., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811021116 · Cited by 43
“With time, these mitochondria accumulate oxidized/damaged proteins and must be recycled (via mitophagy), most likely locally (40, 41).”
BackgroundPINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome
Ahier, A., Dai, C.-Y., Kirmes, I., Cummins, N., Hung, G. C. C., Götz, J., & Zuryn, S. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109203 · Cited by 38
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“The survivability of dopaminergic neurons was shown to be susceptible to mitochondrial dysfunction (Anantharam et al., 2007; Ashrafi et al., 2014; Radad et al., 2006).”
BackgroundGolgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content
Hartwig, C. L., Méndez, G. M., Bhattacharjee, S., Vrailas‐Mortimer, A. D., Zlatic, S. A., Freeman, A. A. H., Gokhale, A., Concilli, M., Werner, E., Savas, C. S., et al. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.1284-20.2020 · Cited by 42
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“Several reports also showed that damaged mitochondria could be removed by mitophagy in the distal part of the axon (Wang et al., 2011; Liu et al., 2012; Ashrafi et al., 2014), suggesting that mitochondria do not need to return to the cell body for targeted degradation of damaged mitochondria.”
BackgroundER-shaping proteins are required for ER and mitochondrial network organization in motor neurons
Fowler, P. C., & O’Sullivan, N. C. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw139 · Cited by 40
“To our knowledge, mitophagy has not been investigated in models of HSP; however, PINK1 and parkin have been shown to maintain mitochondrial health in distal neuronal axons through promoting mitophagy (41).”
BackgroundMechanisms of neuronal survival safeguarded by endocytosis and autophagy
Overhoff, M., Bruyckere, E. D., & Kononenko, N. L. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15194 · Cited by 40
“…Rui et al., 2018) Parkin Mitophagy, autophagy of synaptic vesicle proteins Degradation of dysfunctional mitochondria, regulation of synaptic vesicle endocytosis (Ashrafi et al., 2014; Cao et al., 2014; Gao et al., 2017; Trempe et al., 2009) DJ−1 synaptic vesicle recycling Possible regulation of…”
BackgroundInfluentialSphingolipid metabolism – an ambiguous regulator of autophagy in the brain
van Echten‐Deckert, G., & Alam, S. (2018) · Biological Chemistry · doi:10.1515/hsz-2018-0237 · Cited by 39
Dopaminergic Axons: Key Recitalists in Parkinson’s Disease
Mishra, A. K., & Dixit, A. (2021) · Neurochemical Research · doi:10.1007/s11064-021-03464-1 · Cited by 37
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Grochowska, K. M., Andres‐Alonso, M., Karpova, A., & Kreutz, M. R. (2022) · The EMBO Journal · doi:10.15252/embj.2021110057 · Cited by 38
“Along these lines, organelles such as the ER (Kuijpers et al , 2021), mitochondria (Maday et al , 2012; Ashrafi et al , 2014), and SVs (Hernandez et al , 2012; Binotti et al , 2015; L € uningschro¨r et al , 2017; Hoffmann-Conaway et al , 2020) as well as scaffold proteins like Liprin-a and Syd-1…”
Oxidation of retromer complex controls mitochondrial translation
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The where, what, and when of membrane protein degradation in neurons
Jin, E. J., Kiral, F. R., & Hiesinger, P. R. (2017) · Developmental Neurobiology · doi:10.1002/dneu.22534 · Cited by 38
“Although local degradation of membrane proteins via autophagy has not been directly demonstrated, local degradation of mitochondria through PINK/PARKIN-mediated mitophagy at axon terminals has been reported (Ashrafi et al., 2014).”
BackgroundSurveillance and transportation of mitochondria in neurons
Vanhauwaert, R., Bharat, V., & Wang, X. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.01.015 · Cited by 36
Interplay Between Autophagy and Zinc
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“In this case, mitophagy can occur locally in axons (Ashrafi et al., 2014) to degrade poor mitochondria.”
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“Mitochondrial morphology, respiration and turnover may differ among regions like soma, axons, axon terminals and dendrites (Chang et al., 2006; Ashrafi et al., 2014).”
BackgroundWehnekamp, F., Plucińska, G., Thong, R., Misgeld, T., & Lamb, D. C. (2019) · eLife · doi:10.7554/elife.46059 · Cited by 37
“…with a rapidly expanding set of organelle-targeted biosensors (Breckwoldt et al., 2014) and optogenetic actuators of organelle physiology (Rost et al., 2015; Ashrafi et al., 2014), as well as motor (Gutnick et al., 2019; van Bergeijk et al., 2015) and track (Borowiak et al., 2015) composition.”
Orchestrating mitochondria in neurons: Cytoskeleton as the conductor
Cardanho‐Ramos, C., Faria‐Pereira, A., & Morais, V. A. (2019) · Cytoskeleton · doi:10.1002/cm.21585 · Cited by 37
“Nonetheless, recently it has been observed that PINK1/Parkin-mediated mitophagy indeed occurs in neurons (Ashrafi et al., 2014; Cai, Zakaria, Simone, & Sheng, 2012).”
BackgroundInfluentialHallmarks and Molecular Tools for the Study of Mitophagy in Parkinson’s Disease
Goiran, T., Eldeeb, M. A., Zorca, C. E., & Fon, E. A. (2022) · Cells · doi:10.3390/cells11132097 · Cited by 38
Flies with Parkinson's disease
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Mitophagy’s impacts on cancer and neurodegenerative diseases: implications for future therapies
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“Upon focal acute damage to axonal mitochondria, the PINK1–Parkin pathway is activated, triggering local mitophagy [319].”
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Steer, E. K., Dail, M. K., & Chu, C. T. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6206 · Cited by 35
“Although it had been assumed that autophagy occurs mostly within the neuronal soma, autophagosomes are continually formed at the distal tip of axons (72), sufficient to support mitophagy of photo-irradiated mitochondria (4).”
Selective Neuron Vulnerability in Common and Rare Diseases—Mitochondria in the Focus
Paß, T., Wiesner, R. J., & Pla‐Martín, D. (2021) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.676187 · Cited by 37
“…reported an only moderate Parkin contribution to degradation of damaged mitochondria in primary neurons (Cai et al., 2012; Grenier et al., 2013), whereas others confirmed the importance of Parkin for mitophagy in these cells (Grenier et al., 2014) and especially axons (Ashrafi et al., 2014).”
BackgroundTang, H., Zheng, Z., Wang, H., Wang, L., Zhao, G., & Wang, P. (2022) · Nutrients · doi:10.3390/nu14071504 · Cited by 36
“Its stability is necessary for Parkin to recruit damaged mitochondria and stimulation of mitophagy [38].”
BackgroundSaito, A., & Cavalli, V. (2015) · Molecular & Cellular Proteomics · doi:10.1074/mcp.r115.052753 · Cited by 34
Cao, X., Wang, H., Wang, Z., Wang, Q., Zhang, S., Deng, Y., & Fang, Y. (2017) · Aging Cell · doi:10.1111/acel.12654 · Cited by 36
Pathologic and therapeutic implications for the cell biology of parkin
Charan, R. A., & LaVoie, M. J. (2015) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2015.02.008 · Cited by 32
“axons (Ashrafi et al., 2014), perhaps providing the most convincing demonstration of neuronal mitophagy to date (Lu, 2014).”
BackgroundSelf-citationTumor protein Tctp regulates axon development in the embryonic visual system
Roque, C. G., Wong, H. H., Lin, J. Q., & Holt, C. E. (2016) · Development · doi:10.1242/dev.131060 · Cited by 33
Sensory neuropathy and nociception in rodent models of Parkinson's disease
Valek, L., Auburger, G. W. J., & Tegeder, I. (2019) · Disease Models & Mechanisms · doi:10.1242/dmm.039396 · Cited by 33
Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury
Petrova, V., Nieuwenhuis, B., Fawcett, J. W., & Eva, R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041798 · Cited by 35
Neuronal activity-driven O-GlcNAcylation promotes mitochondrial plasticity
Yu, S. B., Wang, H., Sánchez, R. G., Carlson, N. M., Nguyen, K. Q., Zhang, A. J., Papich, Z. D., Abushawish, A. A., Whiddon, Z. D., Matysik, W., et al. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.05.008 · Cited by 31
Precisely Control Mitochondria with Light to Manipulate Cell Fate Decision
Erñst, P., Xu, N., Qu, J., Chen, H., Goldberg, M. S., Darley-Usmar, V. M., Zhang, J. J., O'Rourke, B. P., Liu, X., & Zhou, L. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.06.038 · Cited by 33
“There has been considerable debate regarding how neurons handle damaged or dysfunctional mitochondria with some studies concluding that Parkin-mediated mitophagy only occurs near mature lysosomes in the cell body and that retrograde transport is required for degradation of distal mitochondria, whereas others conclude…”
BackgroundYu, M., Yang, J., Gao, X., Sun, W., Liu, S., Han, Y., Lu, X., Jin, C., Wu, S., & Cai, Y. (2020) · Metallomics · doi:10.1039/c9mt00291j · Cited by 32
Ubiquitination at the mitochondria in neuronal health and disease
Covill‐Cooke, C., Howden, J. H., Birsa, N., & Kittler, J. T. (2017) · Neurochemistry International · doi:10.1016/j.neuint.2017.07.003 · Cited by 33
“Miro1 phosphorylation is proposed to be important for this process, with reports showing Miro can be phosphorylated by PINK1 (Wang et al., 2011; Weihofen et al., 2009).”
InfluentialRole of Mitochondria–ER Contact Sites in Mitophagy
Rühmkorf, A., & Harbauer, A. B. (2023) · Biomolecules · doi:10.3390/biom13081198 · Cited by 35
“Alternatively, the local fusion of mitophagosomes with axonal lysosomes has been observed [51], but the exact site of neuronal autophagosome–lysosome fusion is still a matter of discussion [52].”
BackgroundAutophagy and lysosomal pathways in nervous system disorders
Bingol, B. (2018) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2018.04.009 · Cited by 32
Yoon, Y. H., Yeon, S. H., Choi, M. R., Jang, Y., Kim, J. A., Oh, H.-W., Xu, J., Park, S. K., Heo, J. Y., Rha, K., et al. (2020) · Allergy Asthma and Immunology Research · doi:10.4168/aair.2020.12.4.653 · Cited by 32
A new method for quantifying mitochondrial axonal transport
Chen, M., Li, Y., Yang, M., Chen, X., Chen, Y., Yang, F., Lu, S., Yao, S.-Y., Zhou, T., Liu, J., et al. (2016) · Protein & Cell · doi:10.1007/s13238-016-0268-3 · Cited by 35
“Nonetheless, our ability to image and quantify axonal mitochondrial transport remains limited, although recent studies have begun to provide insights into these important processes (Ashrafi et al., 2014; Hollenbeck and Grabensee, 1993; Overly and Hollenbeck, 1996; Zhang et al., 2011).”
BackgroundImpaired Autophagy in Motor Neurons: A Final Common Mechanism of Injury and Death
Porras, M. A. G., Sieck, G. C., & Mantilla, C. B. (2018) · Physiology · doi:10.1152/physiol.00008.2018 · Cited by 31
“Autophagosomes can fuse with lysosomes (1) locally at the axon terminal, or be transported retrogradely in the axon and fuse with lysosomes (2) during axon transport or at the cell soma (3).”
BackgroundLian, W., Yang, X., Duan, Q., Li, J., Zhao, Y., Yu, C., He, T., Sun, T., Zhao, Y., & Wang, W. (2024) · Molecules · doi:10.3390/molecules29112516 · Cited by 32
“It has been demonstrated that neuroinflammation and the subsequent neuronal degeneration can be alleviated by regulating the status of microglia [22,23].”
BackgroundClarke, J.-P. W. E., & Mearow, K. M. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23733 · Cited by 30
“…that, by recycling damaged organelles and redundant proteins, the pool of available energy for synthesis of new proteins and organelles within the cell increases, thus allowing DRG axons and cells to survive and grow (Verma et al., 2005; Gumy et al., 2010; Yang et al., 2013; Ashrafi et al., 2014).”
BackgroundAge-related impairment of autophagy in cervical motor neurons
Pareja‐Cajiao, M., Gransee, H. M., Stowe, J. M., Rana, S. D., Sieck, G. C., & Mantilla, C. B. (2020) · Experimental Gerontology · doi:10.1016/j.exger.2020.111193 · Cited by 29
“Aging-related impairment of autophagy in motor neurons and the resulting reduced clearance of damaged cytoplasmic structures, may contribute to altered axonal trafficking (Ashrafi et al., 2014), denervation of muscle fibers (Greising et al.”
BackgroundFranco, R., Rivas‐Santisteban, R., Navarro, G., Pinna, A., & Reyes‐Resina, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094643 · Cited by 31
“Citation: Franco, R.; Rivas- Santisteban, R.; Navarro, G.; Pinna, A.; Reyes-Resina, I. Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage.”
BackgroundInfluentialCai, J., Guan, H., Li, D., Shi, B., Jiang, Y., Qiao, S., Liu, Q., Fang, C., & Zhang, Z. (2023) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2023.109046 · Cited by 29
Boecker, C. A., & Holzbaur, E. L. F. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.01.005 · Cited by 26
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Spastin MIT Domain Disease-Associated Mutations Disrupt Lysosomal Function
Allison, R. J., Edgar, J. R., & Reid, E. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.01179 · Cited by 27
“with defects in these processes linked to axonopathy (Ashrafi et al., 2014; Gowrishankar et al., 2015; Xie et al., 2015).”
BackgroundNew formulation of old aspirin for better delivery
Kalathil, A. A., Kumar, A., Banik, B., Ruiter, T. A., Pathak, R., & Dhar, S. (2015) · Chemical Communications · doi:10.1039/c5cc07316b · Cited by 26
Selective autophagy: The new player in the fight against neurodegenerative diseases?
Wu, M.-Y., Song, J., Wang, S.-F., Cai, C.-Z., Li, M., & Lu, J. (2017) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2017.11.009 · Cited by 27
“Indeed, PINK1 or parkin mutation causes the accumulation of damaged mitochondria in axons in PD patients (Liu et al., 2012a), while ROS induced mitophagy in distal axons of hippocampal neurons has been observed (Ashrafi et al., 2014).”
BackgroundAutophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act
Jiménez-Moreno, N., & Lane, J. D. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/8865611 · Cited by 26
“However, under stress conditions, mitophagy initiation has been reported to also occur along the axon [113].”
BackgroundGrimm, A., Cummins, N., & Götz, J. (2018) · iScience · doi:10.1016/j.isci.2018.07.015 · Cited by 26
“Using such an approach, mt-KR-dependent ROS production has previously been shown to initiate mitophagy locally (Ashrafi et al., 2014; Wang et al., 2012; Yang and Yang, 2011), and to induce the local elimination of photostimulated mt-KR-expressing dendrites and spines (Ertürk et al.”
BackgroundFundamental roles of the Optineurin gene in the molecular pathology of Amyotrophic Lateral Sclerosis
Zhao, S., Chen, R., Gao, Y., Lu, Y., Bai, X., & Zhang, J. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1319706 · Cited by 27
Coupling axonal mRNA transport and local translation to organelle maintenance and function
Vargas, J. N. S., Sleigh, J. N., & Schiavo, G. (2022) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2022.01.008 · Cited by 24
Deubiquitinating Enzymes in Parkinson’s Disease
Chakraborty, J., & Ziviani, E. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00535 · Cited by 26
Mitochondrial transport in neurons and evidence for its involvement in acute neurological disorders
Lu, D., Feng, Y., Liu, G., Yang, Y., Ren, Y., Chen, Z., Sun, X., Guan, Y.-X., & Wang, Z. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1268883 · Cited by 29
“Recent studies have shown that PINK1 mRNA is present in axons (Ashrafi et al., 2014).”
BackgroundDNA repair deficiency in neuropathogenesis: when all roads lead to mitochondria
Bermúdez-Guzmán, L., & Leal, A. (2019) · Translational Neurodegeneration · doi:10.1186/s40035-019-0156-x · Cited by 24
Neurodegenerative disorders associated with genes of mitochondria
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“In normal condition, it interposes the degradation of parkin interaction substrate (PARIS), leading to transcriptional activation of nuclear translocation of PGC1α and mitochondriaassociated genes [38].”
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“Therefore, we tested whether Sestrin2 is associating with mitochondria upon various mitochondriadamaging stresses, including Cu-induced heavy metal stress [66], oxidative stress H2O2 [62], and mild uncoupling with CCCP [50].”
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Autophagy at synapses in neurodegenerative diseases
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Exercise and mitochondrial remodeling to prevent age-related neurodegeneration
O’Reilly, C. L., Miller, B. F., & Lewis, T. L. (2022) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00611.2022 · Cited by 25
Triggering mitophagy with far-red fluorescent photosensitizers
Hsieh, C., Chu, C.-H., Lee, H., & Yang, W. Y. (2015) · Scientific Reports · doi:10.1038/srep10376 · Cited by 23
Parkin overexpression protects retinal ganglion cells against glutamate excitotoxicity.
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Metadata
- 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
- Publisher
- Rockefeller University Press
- Published
- 2014-08-25
- Volume
- 206
- Issue
- 5
- Pages
- 655-670
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC4151150
- 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
- hybrid
- doi.org
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Clinical 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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