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PTEN-induced putative kinase 1 (PINK1) is a mitochondrial serine/threonine-protein kinase encoded by the PINK1 gene.[1][2]
Enzyme Structure[edit]
PINK1 is synthesized as a 63000 Da protein which is often cleaved by PARL, between the 103-Alanine and the 104-Phenylalanine residues, into a 43000 Da fragment.[3] PINK1 contains an N-terminal mitochondrial localization sequence, a putative transmembrane sequence, a Ser/Thr kinase domain, and a C-terminal regulatory sequence. The protein has been found to localize to the outer membrane of mitochondria, but can also be found throughout the cytosol. Experiments suggest the Ser/Thr kinase domain faces outward toward the cytosol, indicating a possible point of interaction with parkin.[4]
Biological Function[edit]
PINK1 is intimately involved with mitochondrial quality control by identifying damaged mitochondria and targeting specific mitochondria for degradation. Healthy mitochondria maintain a membrane potential that can be used to import PINK1 into the inner membrane where it is cleaved by PARL and cleared from the outer membrane. Severely damaged mitochondria lack sufficient membrane potential to import PINK1, which then accumulates on the outer membrane. PINK1 then recruits parkin to target the damaged mitochondria for degradation through autophagy.[5] Due to the presence of PINK1 throughout the cytoplasm, it has been suggested that PINK1 functions as a "scout" to probe for damaged mitochondria.[6]
PINK1 may also control mitochondria quality through mitochondrial fission. Through mitochondrial fission, a number of daughter mitochondria are created, often with an uneven distribution in membrane potential. Mitochondria with a strong, healthy membrane potential were more likely to undergo fusion than mitochondria with a low membrane potential. Interference with the mitochondrial fission pathway led to an increase in oxidized proteins and a decrease in respiration.[7] Without PINK1, parkin cannot efficiently localize to damaged mitochondria, while an over-expression of PINK1 causes parkin to localize to even health mitochondria.[8] Furthermore, mutations in both Drp1, a mitochondrial fission factor, and PINK1 were fatal in Drosophila models. However, an over-expression of Drp1 could rescue subjects deficient in PINK1 or parkin, suggesting mitochondrial fission initiated by Drp1 recreates the same effects of the PINK1/parkin pathway.[9]
In addition to mitochondrial fission, PINK1 has been implicated in mitochondrial motility. The accumulation of PINK1 and recruitment of parkin targets a mitochondria for degradation, and PINK1 may serve to enhance degradation rates by arresting mitochondrial motility. Over-expression of PINK1 produced similar effects to silencing Miro, a protein closely associated with mitochondrial migration.[10]
Another mechanism of mitochondrial quality control may arise through mitochondria-derived vesicles. Oxidative stress in mitochondria can produce potentially harmful compounds including improperly folded proteins or reactive oxygen species. PINK1 has been shown to facilitate the creation of mitochondria-derived vesicles which can separate reactive oxygen species and shuttle them toward lysosomes for degradation.[11]
Disease Relevance[edit]
Parkinson's disease is often characterized by the degeneration of dopaminergenic neurons and associated with the build-up of improperly folded proteins and Lewy bodies. Mutations in the PINK1 protein have been shown to lead to a build-up of such improperly folded proteins in the mitochondria of both fly and human cells.[12] Specifically, mutations in the serine/threonine kinase domain have been found in a number of Parkinson's patients where PINK1 fails to protect against stress-induced mitochondrial dysfunction and apoptosis.[13]
References[edit]
- ^ Unoki M, Nakamura Y (Aug 2001). "Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway". Oncogene. 20 (33): 4457–65. doi:10.1038/sj.onc.1204608. PMID 11494141.
- ^ Valente EM, Salvi S, Ialongo T, Marongiu R, Elia AE, Caputo V, Romito L, Albanese A, Dallapiccola B, Bentivoglio AR (Sep 2004). "PINK1 mutations are associated with sporadic early-onset parkinsonism". Ann Neurol. 56 (3): 336–41. doi:10.1002/ana.20256. PMID 15349860.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ Deas, Emma; Plun-Favreau, Helene; Gandhi, Sonia; Desmond, Howard; Kjaer, Svend; Loh, Samantha H.Y.; Renton, Alan E.M.; Harvey, Robert J.; Whitworth, Alexander J.; Martins, L. Miguel; Abramov, Andrey Y.; Wood, Nicholas W. (2011). "PINK1 cleavage at position A103 by the mitochondrial protease PARL". Hum. Mol. Genet. 20 (5): 867–869. doi:10.1093/hmg/ddq526. PMC 3033179. PMID 21138942.
- ^ Springer, Wolfdieter (2011). "Regulation of PINK1-Parkin mediated mitophagy". Autophagy. 7 (3): 266–278. doi:10.4161/auto.7.3.14348. PMID 21187721. Retrieved 22 February 2014.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Youle, Richard (2012). "Mitochondrial fission, fusion, and stress". Science. 337 (6098): 1062–1065. doi:10.1126/science.1219855. PMC 4762028. PMID 22936770.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Narendra, Derek (2012). "Mitochondrail quality control mediated by PINK1 and Parkin: links to parkinsonism". Cold Spring Harbor. Perspectives in Biology. 4 (11): 1–19. Retrieved 22 February 2014.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Twig, Gilad (2008). "Fission and selective fusion govern mitochondrial segregation and elimination by autophagy". The EMBO Journal. 27 (2): 433–446. doi:10.1038/sj.emboj.7601963. PMC 2234339. PMID 18200046. Retrieved 25 February 2014.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Vivez-Bauza, Cristofol (2010). "PINK1-dependent recruitment of Parkin to mitochondria in mitophagy". Proceedings of the National Academy of Sciences of the United States of America. 107 (1): 378–83. doi:10.1073/pnas.0911187107. PMC 2806779. PMID 19966284.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Poole, Angela C (2008). "The PINK1/Parkin pathway regulates mitochondrial mitophagy". Proceedings of the National Academy of Sciences of the United States of America. 105 (5): 1638–43. doi:10.1073/pnas.0709336105. PMC 2234197. PMID 18230723.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Liu, Song; Sawada, Tomoyo; Lee, Seongsoo; Yu, Wendou; Silverio, George; Alapatt, Philomena; Millan, Ivan; Shen, Alice; Saxton, William; Kanao, Tomoko; Takahashi, Ryosuke; Hattori, Nobutaka; Imai, Yuzuru; Lu, Bingwei (2012). "Parkinson's disease-associated kinase PINK1 regulates Miro protein level and axonal transport of mitochondria". PLOS Genetics. 8 (3): e102537. doi:10.1371/journal.pgen.1002537. PMC 3291531. PMID 22396657.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ Mclelland, Gian-luca (2014). "Parkin and PINK 1 function in a vesicular trafficking pathway regulating mitochondrial quality control". The EMBO Journal. 33 (4): 282–295. Retrieved 22 February 2014.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Pimenta De Castro, I.; Costa, A. C.; Lam, D.; Tufi, R.; Fedele, V.; Moisoi, N.; Dinsdale, D.; Deas, E.; Loh, S H Y.; Martins, L. M. (2012). "Genetic analysis of mitochondrial protein misfolding in Drosophila melanogaster". Cell Death and Differentiation. 19 (8): 1308–16. doi:10.1038/cdd.2012.5. PMC 3392634. PMID 22301916. Retrieved 22 February 2014.
- ^ Valente, E. P. (2004). "Hereditary early-onset Parkinson's disease caused by mutations in PINK1". Science. 304 (5674): 1158–60. doi:10.1126/science.1096284. PMID 15087508. Retrieved 25 February 2014.
{{cite journal}}: Unknown parameter|coauthors=ignored (|author=suggested) (help)
External links[edit]
Further reading[edit]
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