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MitoNews
Mitochondrial Research Bulletin
Published by:
MitoSciences Inc.
Advancing Vital Discoveries in Mitochondrial Research
http://www.mitosciences.com
Edited by:
Roderick Capaldi, D.Phil.
[email protected]
Written by:
Roderick Capaldi, D.Phil.
Volume 04, Issue 04 - September 2008
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Past Issues of MitoNews can be found at:
http://www.mitosciences.com/mitonews_archives.html
MITOCHONDRIAL OXIDATIVE STRESS: THE PATHWAY(S) LINKING
PINK 1, PARKIN, SYNUCLEIN AND DJ1 TO PARKINSONS DISEASE.
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In this Issue:
1. DJ1 AND ITS KEY ROLE IN OXIDATIVE STRESS RESPONSE
2. ALPHA SYNUCLEIN; A MITOCHONDRIAL PROTEIN
3. PINK1 AND PARKIN; MITOCHONDRIAL AND CYTOSOLIC COMPONENTS
OF A COMMON OXIDATIVE STRESS RESPONSE PATHWAY.
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The evidence of mitochondrial involvement in the pathology of Parkinsons disease is now overwhelming. Whether mitochondrial dysfunction contributed by mutations of component proteins, and exacerbated by environmental insults, is causative of the disease, is less defined.
There continues to be rapid and exciting progress toward understanding the roles of several proteins and mutations, in which at least, predispose and accelerate the onset of PD. As each of these is either a mitochondrial protein per se or is able to interact with the organelle directly or indirectly. Below I review some of the new work here.
The four proteins discussed here are DJ1 (also called PARK 7), Pink 1 (PTEN-induced kinase 1), alpha synuclein and parkin. Two recent reviews provide a useful introduction to what is now known about these proteins.
PINK1, PARKIN, DJ1 AND MITOCHONDRIAL DYSFUNCTION IN PARKINSONS DISEASE. Dodson. MW & Guo. M. Current Opinion in Neurobiology 17. 331-7 (2007)
MITOCHONDRIAL ALTERATIONS IN PARKINSONS DISEASE; NEW CLUES. Vila. M., Ramonet. D & Perier C. J Neurochem. In press (2008)
DJ1 AND ITS KEY ROLE IN OXIDATIVE STRESS RESPONSE
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Several studies have helped to clarify the link between DJ1 and mitochondria. DJ1 is a predominantly cytosolic protein known to act as a scavenger of mitochondrial H2O2 through its peroxiredoxin-like peroxidase activity.
DJ1 GENE DELETION REVEALS THAT DJ1 IS AN ATYPICAL PEROXIREDOXIN-LIKE PEROXIDASE. Andrew-Mateos et al. Proc. Natl. Acad. Sci. USA 104. 14807-12 (2007)
Moreover, it has been reported that DJ1 has chaperonine function such that its’ inactivation allows
unwanted cellular protein aggregation (e.g. of synuclein) under oxidative stress.
Recently Junn et al. reported that upon oxidant challenge the levels of DJ1 in
mitochondria increase in a short time frame, followed by a later translocation of the
protein to the nucleus. The basis of the redox properties of DJ1 is oxidation of cys 106.
Mutation of this residue was found not to affect the translocation process.
MITOCHONDRIAL LOCALIZATION OF DJ-1 LEADS TO ENHANCED NEUROPROTECTION Junn. E., Jang. Wh. Zhao. X. Jeong. BS & Mouradian. MM J Neurosci research Aug in press (2008)
The link between the stability of DJ1 and its anti-oxidant role has been examined by Hulleman et al. who showed that the familial mutant associated with early onset PD (L166P) fails to dimerize and is rapidly degraded. They also show that over-oxidation of the wild type protein destabilizes the protein, possibly linking environmental oxidative stress to sporadic PD via altered DJ1.
DESTABILIZATION OD DJ-1 BY FAMILIAL SUBSTITUTION AND OXDIATIVE MODIFICATIONS; IMPLICATIONS FOR PARKINSONS DISEASE.
Hulliman JD et al. Biochemistry 46. 5776-89 (2007)
Also in a recent study using neuroblastoma cells Batelli et al. showed that down regulation of the levels of DJ-1 made these cells more susceptible to oxidative challenge and induced aggregation of alpha synuclein thereby rendering this protein more cytotoxic.
DJ-1 MODILATES ALPHA SYNUCLEIN AGGREGATION STATE IN A CELLULAR MODEL OF OXIDATIVE STRESS. Batelli S et al. Plos One 3 1884 (2008)
It is important to note that DJ1 was originally identified as a novel oncogene and it was shown that the levels of this protein were increased in the plasma of patients with several different cancers. Along with a role in PD, alteration of DJ1 may be a factor in another common late-onset disease, inclusion body myositis. DJ1 was found to be increased in total, and higher in mitochondria as well as highly oxidized in the muscles of patients with this condition.
IN INCLUSION BODY MYOSITIS MUSCLE FIBERS PARKINSON-ASSOCIATED DJ-1 IS INCREASED AND OXIDISED. Terracciano C. et al. Free Radic. Biol. Med. June in press (2008)
ALPHA SYNUCLEIN; A MITOCHONDRIAL PROTEIN
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Further confirming the view I now hold that mitochondria are the center of all good and evil (healthwise), two recent studies show the more direct link between alpha synuclein and our favorite black hole than previously thought.
In an exciting recent paper (not only for the extensive use of MitoSciences antibodies!) Devi et al. show the import and accumulation of alpha synuclein in human dopaminergic neuronal cells and a subsequent selective effect on Complex I activity through direct association with the complex. Also Cole et al. recently showed mitochondrial translocation of alpha synuclein which they were able to show required acidification of the cytosol, a pH change known to occur with oxidative or metabolic stress.
MITOCHONDRIAL IMPORT AND ACCUMULATION OF ALPHA SYNUCLEIN IMPAIR COMPLEX I IN HUMAN DOPAMINERGIC NEURONAL CULTURES AND PARKINSON DISEASE BRAIN.
Devi L. et al. J. Biol Chem 283 9089-9100 (2008)
MITOCHONDRIAL TRANSLOCATION OF ALPHA SYNUCLEIN IS PROMOTED BY INTRACELLULAR ACIDIFICATION. Cole N.B et al Exp. Cell Research314. 2076-89 (2008)
PINK1 AND PARKIN; MITOCHONDRIAL AND CYTOSOLIC COMPONENTS OF A COMMON OXIDATIVE STRESS RESPONSE PATHWAY.
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Progress in understanding, the role of, and targets involved in the action of the mitochondrial kinase Pink1 or PTEN1 has been slow until recently when two separate but probably overlapping roles were described. One is protection against oxidative stress and the second is the regulation of mitochondrial morphology. Pridgeon et al. reported that an important cellular and mitochondrial target for phosphorylation by Pink 1 is the TNF receptor associated protein (TRAP 1) also known as heat shock protein 75, a well defined mitochondrial chaperonin. These authors show that Pink 1 associates with and phosphorylates TRAP 1 to protect the cells from oxidative stress-induced apoptosis.
PINK1 PROTECTS AGAINST OXIDATIVE STRESS BY PHOSPHORYLATING MITOCHONDRIAL CHAPERONE TRAP1 Pridgeon JW., Olzmann J.A. Chin L-S & Li L. Plos Biology 5. E172 (2007)
Other recent reports show a distinct relationship between Pink 1and mitochondrial morphology changes. Over-expression of Pink1 promotes mitochondrial fission while inhibition of expression leads to excessive fusion.
PINK 1 REGULATES MITOCHONDRIAL DYNAMICS THROUGH INTERACTION WITH THE FISSION/FUSION MACHINERY
Yang Y. et al. Proc. Natl. Acad Sci. USA 105. 7070-5 (2008)
The loss of function caused by Pink1 inactivation in human cell lines (and in flies) has recently been rescued by parkin. To date all of the evidence is that parkin is localized to the cytosol so that the link between Pink1 and parkin must be an indirect one. For example parkin may rescue Pink1 deficiency by overcoming the oxidative stress caused by the loss of Pink1 function.
LOSS OF FUNCTION OF HUMAN PINK1 RESULTS IN MITOCHONDRIAL PATHOLOGY AND CAN BE RESCUED BY PARKIN. Exner N. et al. J of neuroscience 27. 12413-8 (2007)
THE PINK 1/PARKIN PATHWAY REGULATES MITOCHONDRIAL MORPHOLOGY. Poole AC et al. Proc Natl. Acad Sci USA 105. 1638-43 (2008)
In summary the recent data on the key proteins in PD (above) provide a compelling story of the constant cellular battle that is oxidative stress and the importance of protecting mitochondria from themselves!
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