The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy
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Protein aggregates and damaged organelles are tagged with ubiquitin chains to trigger selective autophagy. To initiate mitophagy, the ubiquitin kinase PINK1 phosphorylates ubiquitin to activate the ubiquitin ligase parkin, which builds ubiquitin chains on mitochondrial outer membrane proteins, where they act to recruit autophagy receptors. Using genome editing to knockout five autophagy receptors in HeLa cells, here we show that two receptors previously linked to xenophagy, NDP52 and optineurin, are the primary receptors for PINK1- and parkin-mediated mitophagy. PINK1 recruits NDP52 and optineurin, but not p62, to mitochondria to activate mitophagy directly, independently of parkin. Once recruited to mitochondria, NDP52 and optineurin recruit the autophagy factors ULK1, DFCP1 and WIPI1 to focal spots proximal to mitochondria, revealing a function for these autophagy receptors upstream of LC3. This supports a new model in which PINK1-generated phospho-ubiquitin serves as the autophagy signal on mitochondria, and parkin then acts to amplify this signal. This work also suggests direct and broader roles for ubiquitin phosphorylation in other autophagy pathways.
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ATG9A has been linked to OPTN, which plays an important role as an adapter for PINK1-PRKN mitophagy.
“has been linked to OPTN, which plays an important role as an adapter for PINK1-PRKN mitophagy [12, 34, 35].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [12]
The 'Autophagy receptors in mitophagy' section (page not provided) shows that OPTN helps mediate Parkin-associated mitophagy, redundantly with NDP52. Our copy does not establish a link between ATG9A and OPTN; ATG9A appears only in the title of a work listed in the References. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMitochondrial pS65-Ub chains serve as a specific signal for engulfment of mitochondria in autophagosomes.
“These serve as a specific signal for the engulfment of mitochondria in autophagosomes [12].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [12]
pUbS65 accumulates with mitochondrial stress, age, and disease and serves as a specific signal for recognition by autophagy receptors.
“Moreover, pUbS65 has been suggested to accumulate with mitochondrial stress, age, and disease [19] and to serve as a specific signal for recognition by autophagy receptors [20, 21].”
From miR-27a and miR-27b regulate autophagic clearance of damaged mitochondria by targeting PTEN-induced putative kinase 1 (PINK1) (2016) · cites this paper as [21]
In vitro, silencing of TBK1 or ALS-related TBK1 variants reduces the recruitment of OPTN and LC3B to damaged mitochondria, thereby impairing mitophagy and resulting in the accumulation of defective mitochondria.
“In vitro, silencing of TBK1 or ALS-related TBK1 variants reduces the recruitment of OPTN and LC3B to damaged mitochondria [212,213], thereby impairing mitophagy and resulting in the accumulation of defective mitochondria (Figure 1).”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [212]
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Mitochondrial degradation: Mitophagy and beyond
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Self-citationDisease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria
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Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases
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Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency
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Mechanisms of Selective Autophagy in Normal Physiology and Cancer
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The biosynthesis, signaling, and neurological functions of bile acids
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Autophagy in stem cells: repair, remodelling and metabolic reprogramming
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The Autophagy Lysosomal Pathway and Neurodegeneration
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Autophagy and ALS: mechanistic insights and therapeutic implications
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“In vitro, silencing of TBK1 or ALS-related TBK1 variants reduces the recruitment of OPTN and LC3B to damaged mitochondria [212,213], thereby impairing mitophagy and”
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Autophagy regulates lipid metabolism through selective turnover of NCoR1
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Self-citationPink1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy
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The RNA-Binding Protein PUM2 Impairs Mitochondrial Dynamics and Mitophagy During Aging
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Dual role of USP30 in controlling basal pexophagy and mitophagy
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“Moreover, pUb has been suggested to accumulate with mitochondrial stress, age, and disease [19] and to serve as a specific signal for recognition by autophagy receptors [20, 21].”
BackgroundLoss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain
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Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons
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“In non-neuronal cells, OPTN, NDP52, and TAX1BP1 are proposed to mediate the autophagic clearance of damaged mitochondria, while p62 clusters organelles without directly facilitating mitophagy (Heo et al., 2015; Lazarou et al., 2015; Moore and Holzbaur, 2016; Narendra et al., 2010a; Wong and Holzbaur, 2014a).”
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Mitophagy Directs Muscle-Adipose Crosstalk to Alleviate Dietary Obesity
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Exercise and mitochondrial dynamics: keeping in shape with ROS and AMPK
Trewin, A., Berry, B., & Wojtovich, A. (2018) · Antioxidants · doi:10.3390/antiox7010007 · Cited by 129 · see citing works
Mitophagy in Acute Kidney Injury and Kidney Repair
Wang, Y., Cai, J., Tang, C., & Dong, Z. (2020) · Cells · doi:10.3390/cells9020338 · Cited by 130 · see citing works
Mitochondrial quality control by the Pink1/Parkin system
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Mitophagy and cGAS–STING crosstalk in neuroinflammation
Zhou, X., Wang, J., Yu, L., Qiao, G., Qin, D., Yuen-Kwan Law, B., Ren, F., Wu, J., & Wu, A. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.05.012 · Cited by 131 · see citing works
Polyphenols as Caloric Restriction Mimetics Regulating Mitochondrial Biogenesis and Mitophagy
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PINK1: The guard of mitochondria
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Self-citationMicroglial mitophagy mitigates neuroinflammation in Alzheimer's disease
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Glucocorticoid impairs mitochondrial quality control in neurons
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Rubicon: <scp>LC</scp>3‐associated phagocytosis and beyond
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Mitochondrial dynamics in cancer-induced cachexia
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Mitochondrial Dysfunction in Skeletal Muscle Pathologies
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Preserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration
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Toward understanding genomic instability, mitochondrial dysfunction and aging
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The Role of Mitophagy in Regulating Cell Death
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Self-citation
- Authors
- Lazarou, M., Sliter, D. A., Kane, L. A., Sarraf, S. A., Wang, C., Burman, J. L., Sideris, D. P., Fogel, A. I., & Youle, R. J.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Youle, Richard J.
- ORCID
- Venue
- Nature
- Published
- 2015-08
- Volume
- 524
- Issue
- 7565
- Pages
- 309-314
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5018156
- OpenAlex
- W2103230459
- Cited by
- 2,774
- References
- 42
- Citations by year
- 2026: 250 · 2025: 304 · 2024: 291 · 2023: 244 · 2022: 268 · 2021: 329 · 2020: 254 · 2019: 221 · 2018: 207 · 2017: 206 · 2016: 177 · 2015: 21
- FWCI
- 160.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- National Institute of Neurological Disorders and Stroke (Z01NS002859)
- 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
- PINK1, Parkin, mitophagy, selective autophagy, autophagy receptors, NDP52, optineurin, ubiquitin phosphorylation, ULK1, WIPI1, p62, LC3, mitochondrial quality control, autophagy initiation, xenophagy
- MeSH terms
- Autophagy-Related Proteins, Autophagy-Related Protein-1 Homolog, PTEN-Induced Putative Kinase, Autophagy, Carrier Proteins, HeLa Cells, Humans, Membrane Proteins, Microtubule-Associated Proteins, Mitochondria, Models, Biological, Nuclear Proteins, Phosphorylation, Protein Kinases, Signal Transduction, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Mitochondrial Proteins, Ubiquitin, Membrane Transport Proteins, Transcription Factor TFIIIA, Ubiquitin-Protein Ligases, Intracellular Signaling Peptides and Proteins, Mitophagy
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