Mitochondrial processing peptidase regulates PINK1 processing, import and Parkin recruitment
Open accessAbstract
Mutations in phosphatase and tensin homologue-induced kinase 1 (PINK1) cause recessively inherited Parkinson's disease (PD), a neurodegenerative disorder linked to mitochondrial dysfunction. In healthy mitochondria, PINK1 is rapidly degraded in a process involving both mitochondrial proteases and the proteasome. However, when mitochondrial import is compromised by depolarization, PINK1 accumulates on the mitochondrial surface where it recruits the PD-linked E3 ubiquitin ligase Parkin from the cytosol, which in turn mediates the autophagic destruction of the dysfunctional organelles. Using an unbiased RNA-mediated interference (RNAi)-based screen, we identified four mitochondrial proteases, mitochondrial processing peptidase (MPP), presenilin-associated rhomboid-like protease (PARL), m-AAA and ClpXP, involved in PINK1 degradation. We find that PINK1 turnover is particularly sensitive to even modest reductions in MPP levels. Moreover, PINK1 cleavage by MPP is coupled to import such that reducing MPP activity induces PINK1 accumulation at the mitochondrial surface, leading to Parkin recruitment and mitophagy. These results highlight a new role for MPP in PINK1 import and mitochondrial quality control via the PINK1–Parkin pathway.
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PINK1 stabilization on depolarized mitochondria results from impaired mitochondrial import and proteolytic processing, allowing full-length PINK1 to accumulate at the outer mitochondrial membrane.
“PINK1 stabilization on depolarized mitochondria results from impaired mitochondrial import and proteolytic processing, allowing full-length PINK1 to accumulate at the outer mitochondrial membrane [57, 58].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [58]
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BackgroundPINK1 drives Parkin self-association and HECT-like E3 activity upstream of mitochondrial binding
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“PINK1 is imported into mitochondria, cleaved by PARL in the inner mitochondrial membrane (IMM), then degraded to restrict its expression (Whitworth et al., 2008; Jin et al., 2010; Deas et al., 2011; Meissner et al., 2011; Greene et al., 2012).”
Sun, Y., Vashisht, A. A., Tchieu, J. H., Wohlschlegel, J. A., & Dreier, L. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.419721 · Cited by 244 · see citing works
Loss of Mitochondrial Function Impairs Lysosomes
Demers-Lamarche, J., Guillebaud, G., Tlili, M., Todkar, K. J., Bélanger, N., Grondin, M., Nguyen, A., Michel, J. J. C., & Germain, M. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.695825 · Cited by 242 · see citing works
The Role of Mitophagy in Innate Immunity
Gkikas, I., Palikaras, K., & Tavernarakis, N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01283 · Cited by 244 · see citing works
The ubiquitin signal and autophagy: an orchestrated dance leading to mitochondrial degradation
Yamano, K., Matsuda, N., & Tanaka, K. (2016) · EMBO Reports · doi:10.15252/embr.201541486 · Cited by 239 · see citing works
“Alternatively, other proteases in the mitochondria such as ClpXP and m-AAA may also function in rapid PINK1 turnover [103] (Fig 3A).”
Mitophagy pathways in health and disease
Killackey, S. A., Philpott, D. J., & Girardin, S. E. (2020) · The Journal of Cell Biology · doi:10.1083/jcb.202004029 · Cited by 236 · see citing works
Barazzuol, L., Giamogante, F., Brini, M., & Calí, T. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21051772 · Cited by 238 · see citing works
“Presenilin-associated rhomboid-like (PARL) is an IMM-resident protease that subsequently cleaves PINK1 in the TM domain between Ala103 and Phe104 [25], producing a truncated 52 kDa protein (the full-length protein is 64 kDa) that is retro-translocated to the cytoplasm and degraded via the N-end rule proteasomal pathwa…”
BackgroundKang, J., Hong, J., & Lee, S. (2016) · Journal of Pineal Research · doi:10.1111/jpi.12319 · Cited by 231 · see citing works
“This initiates the localization of damaged mitochondria to membranes containing LC3, leading to the formation of autophagosomes, followed by fusion with lysosomes and clearance from cells [52].”
BackgroundGrasso, D., Zampieri, L. X., Capelôa, T., de Velde, J. A. V., & Sonveaux, P. (2020) · Cell Stress · doi:10.15698/cst2020.06.221 · Cited by 231 · see citing works
Organellophagy: Eliminating cellular building blocks via selective autophagy
Okamoto, K. (2014) · The Journal of Cell Biology · doi:10.1083/jcb.201402054 · Cited by 218 · see citing works
Neuronal Mitophagy in Neurodegenerative Diseases
Martínez‐Vicente, M. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00064 · Cited by 216 · see citing works
“Once PINK1 reaches the IMM, it is cleaved by mitochondrial matrix proteases such as mitochondrial processing peptidase (MPP) and presenilin-associated rhomboid-like protease (PARL), with the resulting cleaved protein externalized to the cytosol where it is degraded by the UPS (Jin et al., 2010; Deas et al., 2011; Gree…”
BackgroundInfluentialDysfunctional Mitochondria and Mitophagy as Drivers of Alzheimer’s Disease Pathogenesis
Chakravorty, A., Jetto, C. T., & Manjithaya, R. R. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00311 · Cited by 219 · see citing works
“…IMM, it is processed by two proteases, MPP (matrix processing peptidase) and PARL (rhomboid protease presenilinassociated rhomboid-like), thereby making it a substrate for N-end rule degradation by the cytosolic UPS (Jin et al., 2010; Deas et al., 2011; Greene et al., 2012; Yamano and Youle, 2013).”
BackgroundMechanisms and roles of mitophagy in neurodegenerative diseases
Wang, Y., Liu, N., & Lu, B. (2019) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13140 · Cited by 214 · see citing works
A Ubl/ubiquitin switch in the activation of Parkin
Sauvé, V., Lilov, A., Seirafi, M., Vranas, M., Rasool, S., Kozlov, G., Sprules, T. J., Wang, J., Trempe, J., & Gehring, K. (2015) · The EMBO Journal · doi:10.15252/embj.201592237 · Cited by 208 · see citing works
“Parkin is a member of the RBR (RING-in-between-RING) ligase family, which uses a RING/HECT hybrid mechanism to transfer ubiquitin from an E2 enzyme to a substrate via a thioester intermediate (Wenzel et al , 2011).”
Iorio, R., Celenza, G., & Petricca, S. (2021) · Cells · doi:10.3390/cells11010030 · Cited by 218 · see citing works
Kotiadis, V. N., Duchen, M. R., & Osellame, L. D. (2013) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2013.10.041 · Cited by 212 · see citing works
Parkin-catalyzed Ubiquitin-Ester Transfer Is Triggered by PINK1-dependent Phosphorylation
Iguchi, M., Kujuro, Y., Okatsu, K., Koyano, F., Kosako, H., Kimura, M., Suzuki, N., Uchiyama, S., Tanaka, K., & Matsuda, N. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.467530 · Cited by 209 · see citing works
Mitochondrial Dysfunction in Huntington’s Disease
Carmo, C., Naia, L., Lopes, C., & Rego, A. C. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-71779-1_3 · Cited by 209 · see citing works
Critical role of mitochondrial ubiquitination and the OPTN–ATG9A axis in mitophagy
Yamano, K., Kikuchi, R., Kojima, W., Hayashida, R., Koyano, F., Kawawaki, J., Shoda, T., Demizu, Y., Naito, M., Tanaka, K., et al. (2020) · Journal of Cell Biology · doi:10.1083/jcb.201912144 · Cited by 205 · see citing works
“…to a loss in the mitochondrial membrane potential, PINK1, which is rapidly degraded by the proteasome under normal conditions (Deas et al., 2011; Greene et al., 2012; Jin et al., 2010; Yamano and Youle, 2013), accumulates on the outer mitochondrial membrane (OMM; Hasson et al., 2013; Lazarou et…”
Truban, D., Hou, X., Caulfield, T. R., Fiesel, F. C., & Springer, W. (2016) · Journal of Parkinson’s Disease · doi:10.3233/jpd-160989 · Cited by 237 · see citing works
“Though both genes are ubiquitously expressed, complete loss of either function results in selective loss of DA neurons and manifestation of tremor, bradykinesia, and rigidity.”
BackgroundOxidative Stress-Induced Signaling Pathways Implicated in the Pathogenesis of Parkinson’s Disease
Gaki, G. S., & Papavassiliou, A. G. (2014) · NeuroMolecular Medicine · doi:10.1007/s12017-014-8294-x · Cited by 200 · see citing works
“…SOD Superoxide dismutase STAT Signal transducer and activator of transcription SVZ Subventricular zone TCF/ LEF T-cell factor/lymphoid enhancer-binding factor TNF-a Tumor necrosis factor alpha TRAP1 TNF receptor-associated protein UPS Ubiquitin–proteasome system DWm Mitochondrial membrane potential”
BackgroundMitochondrial proteostasis in the context of cellular and organismal health and aging
Moehle, E. A., Shen, K., & Dillin, A. G. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.tm117.000893 · Cited by 193 · see citing works
“In the absence of stress, PINK1 is imported and constitutively degraded; this occurs either by protease degradation in the mitochondrial matrix (97, 98) or by cleavage by the IMS-localized protease PARL followed by translocation to the cytoplasm and N-end rule pathway degradation by the proteasome (Fig.”
BackgroundFranco-Iborra, S., Vila, M., & Perier, C. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00342 · Cited by 194 · see citing works
“Briefly, PINK1 is constitutively imported inside healthy mitochondria, cleaved (Whitworth et al., 2008; Jin et al., 2010; Meissner et al., 2011; Greene et al., 2012) and degraded by the proteasome (Yamano and Youle, 2013), so upon mitochondrial protein import impairment, PINK1 accumulates in the outer membrane of the…”
BackgroundMitochondrial quality control mechanisms as molecular targets in diabetic heart
Chang, X., Li, Y., Cai, C., Wu, F., He, J., Zhang, Y., Zhong, J., Tan, Y., Liu, R., Zhu, H., et al. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155313 · Cited by 192 · see citing works
Gispert, S., Parganlija, D., Klinkenberg, M., Dröse, S., Wittig, I., Mittelbronn, M. G. A., Grzmil, P., Koob, S., Hamann, A., Walter, M. J., et al. (2013) · Human Molecular Genetics · doi:10.1093/hmg/ddt338 · Cited by 188 · see citing works
“proteases, as HTRA2, PARL, the SPG7 / AFG3L2 subunits of the m-AAA complex, as well as OPA1, were also implicated in age-associated neurodegeneration syndromes (26) such as Parkinson’s disease (27-29), spinocerebellar ataxia (30, 31), spastic ataxia – neuropathy”
BackgroundPatel, A. S., Song, J. W., Chu, S. G., Mizumura, K., Osorio, J. C., Shi, Y., El‐Chemaly, S., Lee, C. G., Rosas, I. O., Elias, J. A., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0121246 · Cited by 186 · see citing works
“In healthy mitochondria, PINK1 is constitutively imported to the inner membrane, where it is cleaved by several proteases and ultimately proteolytically degraded[7,8,9].”
BackgroundPalikaras, K., Daskalaki, I., Markaki, M., & Tavernarakis, N. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.04.005 · Cited by 175 · see citing works
“Interestingly, MPP availability is crucial for mitophagy onset due to the tight regulation imposed on PINK1, stretching the need for a strictly controlled system (Greene et al., 2012).”
BackgroundXian, H., & Liou, Y. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-00657-z · Cited by 166 · see citing works
Arena, G., Gelmetti, V., Torosantucci, L., Vignone, D., Lamorte, G., Rosa, P. D., Cilia, E., Jonas, E. A., & Valente, E. M. (2013) · Cell Death and Differentiation · doi:10.1038/cdd.2013.19 · Cited by 162 · see citing works
“Despite we found a strong interaction between overexpressed PINK1 and Bcl-xL, the binding between the two endogenous protein was undetectable in healthy cells, probably because PINK1 is actively and continuously cleaved by voltage-dependent mitochondrial proteases.(24) Indeed, other groups also failed to demonstrate t…”
BackgroundRole and mechanisms of autophagy in acetaminophen‐induced liver injury
Chao, X., Wang, H., Jaeschke, H., & Ding, W. (2018) · Liver International · doi:10.1111/liv.13866 · Cited by 163 · see citing works
Selective escape of proteins from the mitochondria during mitophagy
Saita, S., Shirane, M., & Nakayama, K. I. (2013) · Nature Communications · doi:10.1038/ncomms2400 · Cited by 161 · see citing works
Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder
Lü, W., Karuppagounder, S. S., Springer, D., Allen, M. D., Zheng, L., Chao, B. N., Zhang, Y., Dawson, V. L., Dawson, T. M., & Lenardo, M. J. (2014) · Nature Communications · doi:10.1038/ncomms5930 · Cited by 161 · see citing works
TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics
Davis, S. A., Itaman, S., Janney, C., Sherard, J. A., Dowell, J. A., Cairns, N. J., & Gitcho, M. A. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.04.053 · Cited by 159 · see citing works
“We chose to focus on mitochondrial processing peptidase (MPP), presenilinassociated rhomboid-like protease (PARL), and ATPase family gene 3-like 2 (AFG3L2) because they were shown to affect degradation of phosphatase and tensin homologue-induced kinase 1 (PINK1), which recruits Parkin to mitochondrial membranes during…”
Mitophagy in Cerebral Ischemia and Ischemia/Reperfusion Injury
Shen, L., Gan, Q., Yang, Y., Reis, C., Zhang, Z., Xu, S., Zhang, T., & Sun, C. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.687246 · Cited by 157 · see citing works
“However, the depletion of PHB2 upon OMM rupture destabilizes PINK1 through the activation of PARL and therefore leads to cleavage of fulllength PGAM5 (Yan et al., 2020).”
BackgroundMitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis
Liu, L., Li, Y., Wang, J., Zhang, D., Wu, H., Li, W., Wei, H., Ta, N., Fan, Y., Liu, Y., et al. (2021) · EMBO Reports · doi:10.15252/embr.202050629 · Cited by 157 · see citing works
“C), which indicates the protein level of PINK1 is regulated by post-transcriptional mechanism (Jin et al , 2010; Greene et al , 2012; Cairo et al , 2019).”
Jin, G., Xu, C. S., Zhang, X., Long, J., Rezaeian, A. H., Liu, C., Furth, M. E., Kridel, S. J., Pasche, B., Bian, X., et al. (2017) · Nature Immunology · doi:10.1038/s41590-017-0002-1 · Cited by 153 · see citing works
Mohanty, A., Tiwari-Pandey, R., & Pandey, N. R. (2019) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-019-00507-9 · Cited by 157 · see citing works
The TOMM machinery is a molecular switch in PINK1 and PARK2/PARKIN-dependent mitochondrial clearance
Bertolin, G., Ferrando-Miguel, R., Jacoupy, M., Traver, S., Grenier, K., Greene, A. W., Dauphin, A., Waharte, F., Bayot, A., Salamero, J., et al. (2013) · Autophagy · doi:10.4161/auto.25884 · Cited by 154 · see citing works
“PMPC processes mitochondrial preproteins by cleaving their MTS; it is thought to be essential for mitochondrial import, including that of PINK1.(22,23,32) Contrary to downregulation of TOMM40 or TOMM22, moderate downregulation of PMPCB did not result in a massive loss of mitochondrial markers after CCCP treatment: no…”
BackgroundInfluentialSelf-citationMitochondrial dysfunction in cardiac aging
Tocchi, A., Quarles, E. K., Basisty, N., Gitari, L., & Rabinovitch, P. S. (2015) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2015.07.009 · Cited by 151 · see citing works
Mitophagy links oxidative stress conditions and neurodegenerative diseases
Jung, J., Huh, Y., Shefa, U., Jeong, N., Song, I., Chung, H.-J., & Kim, D. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.249218 · Cited by 152 · see citing works
“Previous studies in Drosophila melanogaster have demonstrated that PINK1 and PARKIN function in the same ge-netic pathway to maintain mitochondrial network integrity (Greene et al., 2012).”
Parkin and mitochondrial quality control: toward assembling the puzzle
Winklhofer, K. F. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.01.001 · Cited by 149 · see citing works
Ju, W., Perkins, G. A., Keun-young Kim, A., Bastola, T., Choi, W.-Y., & Choi, S. (2022) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2022.101136 · Cited by 148 · see citing works
“The fragment of its N-terminal end is then degraded by the ubiquitin–proteasome system (Greene et al., 2012; Okatsu et al., 2015).”
Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility
Shlevkov, E., Kramer, T., Schapansky, J., LaVoie, M. J., & Schwarz, T. L. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612283113 · Cited by 145 · see citing works
Regulation of mitochondrial dynamics in astrocytes: Mechanisms, consequences, and unknowns
Jackson, J. G., & Robinson, M. B. (2017) · Glia · doi:10.1002/glia.23252 · Cited by 144 · see citing works
“Mitochondrial damage or collapse of the mitochondrial matrix potential (Dwm) results in the accumulation of Pink1 (due to the loss of the inner-mitochondrial membrane localized protease presenilin-associated rhomboid-like protein (PARL)-mediated Pink1 degradation) and the subsequent recruitment of parkin from the cyto…”
BackgroundUrolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions
Hou, Y., Chu, X., Park, J., Zhu, Q., Hussain, M., Li, Z., Madsen, H. B., Yang, B., Wei, Y., Wang, Y., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13847 · Cited by 145 · see citing works
A Mitocentric View of Parkinson's Disease
Haelterman, N. A. T., Yoon, W. H., Sandoval, H., Jaiswal, M., Shulman, J. M., & Bellen, H. J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014317 · Cited by 138 · see citing works
“Within the MIM, it is cleaved by two proteins [mitochondrial processing peptidase (Greene et al. 2012) and presenilin-associated rhomboid-like protease ( Jin et al.”
BackgroundAutophagy in neurodegeneration: New insights underpinning therapy for neurological diseases
Corti, O., Blomgren, K., Poletti, A., & Beart, P. M. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15002 · Cited by 141 · see citing works
“…PINK1 and Parkin jointly regulate immune-related mechanisms, which is of particular interest, considering the neuroinflammatory component in PD (Greene et al. 2005, Manzanillo et al. 2013, Matheoud et al. 2016, Torres-Odio et al. 2017, Sun et al. 2018, Kim et al. 2014, Kang et al. 2016, Zhong…”
Background
- Authors
- Greene, A. W., Grenier, K., Aguileta, M. A., Muise, S., Farazifard, R., Haque, M. E., McBride, H. M., Park, D. S., & Fon, E. A.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- University of Ottawa (CA)
- Corresponding author
- Fon, Edward A
- Venue
- The EMBO Reports
- Published
- 2012-02-21
- Volume
- 13
- Issue
- 4
- Pages
- 378-385
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC3321149
- OpenAlex
- W2064127635
- Cited by
- 711
- References
- 23
- Citations by year
- 2026: 27 · 2025: 59 · 2024: 57 · 2023: 39 · 2022: 68 · 2021: 81 · 2020: 57 · 2019: 41 · 2018: 53 · 2017: 43 · 2016: 44 · 2015: 45 · 2014: 35 · 2013: 41 · 2012: 20
- FWCI
- 29.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- EMBO Reports (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Library and Archives Canada (Government of Canada) (submittedVersion)
- eScholarship@McGill (McGill) (submittedVersion)
- McGill-DEV
- Funders
- Heart and Stroke Foundation of Canada
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- mitochondrial processing peptidase, PINK1, Parkin, Parkinson's disease, mitochondrial quality control, mitophagy, mitochondrial protein import, PARL, m-AAA protease, ClpXP, mitochondrial protease, E3 ubiquitin ligase, RNAi screen
- MeSH terms
- ATPases Associated with Diverse Cellular Activities, Mitochondrial Processing Peptidase, PTEN-Induced Putative Kinase, Autophagy, Carbonyl Cyanide m-Chlorophenyl Hydrazone, Humans, Metalloendopeptidases, Mitochondria, Molecular Weight, Peptide Fragments, Protein Kinases, Protein Processing, Post-Translational, Protein Transport, RNA, Small Interfering, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, ATP-Dependent Proteases, Endopeptidase Clp, Gene Knockdown Techniques, HEK293 Cells
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