Resources > MitoNews > Archives > Volume 04, Issue 03 - August, 2008

Volume 04, Issue 03 - August, 2008




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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.
rcapaldi@mitosciences.com

Written by:
Roderick Capaldi, D.Phil.
Volume 04, Issue 03 - August 2008
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Past Issues of MitoNews can be found at:
http://www.mitosciences.com/mitonews_archives.html

RECENT COMINGS, LEAVINGS AND SOME STAYINGS OF
PROTEINS TO, IN AND FROM MITOCHONDRIA.
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In this Issue:

1. Granzyme A, Complex I, and apoptosis; the key role of the OXPHOS complex in ROS mediated cell death

2. Huntingtons disease and trafficking of mutant huntingtin to mitochondria

3. Transcription factors and nuclear receptors and their involvement in mitochondrial events

4. Repairing H2O2 induced mtDNA damage; import of the bases excision repair enzyme APE/ref1 to mitochondria

5. Linking breast cancer with control of apoptosis at the mitochondrion

6. Raf-1 (also called raf-C), a serine/threonine kinase, is targeted to mitochondria to prevent stress mediated apoptosis

7. P66Shc, lifespan and mitochondria; the oxidative stress connection.
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How times are changing. The essentially static picture of a bean shaped organelle called a mitochondrion is all but gone (except for most textbooks). Instead we now perceive this organelle as a pleomorphic, highly dynamic structure ranging from an extensive reticulum to a multitude of small unit mitochondria. There has been considerable effort over the last 5 years+ to define the mitochondrial proteome. As this work has progressed it has become more and more clear that not only the shape but also the composition of mitochondria is dynamic. We have known for some time that a number of proteins such as bax, bim and the like redistribute from the cytosol to the mitochondrion as part of the initiation of apoptosis. Also there are extensive data on the exodus of cytochrome c, AIF, Smac-Diablo and others out of the organelle in the cell death program. The following highlights several proteins for which there is emerging evidence that they redistribute as part of cellular events between compartments, including the mitochondrion. Not surprisingly, perhaps, most are transcription factor and their activators, kinases and proteases.


GRANZYME A, COMPLEX I, AND APOPTOSIS; THE KEY ROLE OF THE OXPHOS COMPLEX IN ROS MEDIATED CELL DEATH.
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In a remarkable article in Cell recently, Martinvalet et al. show that the protease Granzyme A is able to enter mitochondria by a mechanism as yet undefined but not a typical protein import pathway, and cleave Complex I to induce apoptosis. The entry of the protease does not perturb normal mitochondrial functioning until there is a build up of ROS due to the inhibition of Complex I. These workers identified the site of complex I cleavage as NDUFS3
Ref. MARTINVALET.D., DYKXHOORN. DM., FERRINI.R & LIEBERMAN J. CELL
For more information on the Granzymes read CHOWDBURY D & LIEBERMAN.J. Ann.Rev. of Immunol 26. 389-420 (2008)

This finding adds to the number of proteases now found to cleave complex I to induce ROS activated apoptosis.
The first such observation identified NDUFS1 as the target of a caspase 3 early in apoptosis
Ref. RICCI. JE., MUNOZ-PINEDO.C.,FITZGERALD.P., BAILLY-MAITRE.B., PERKINDS.GA., YADAVA.N., SCHEFFLER. IE., ELLISMAN. MH & GREEN.DR Cell 117, 773-86 (2204)

It has also been reported that calpain 10 is able to cleave Complex I. According to Arrington et al. calpain10, either endogenous to the mitochondrial matrix or translocated there transiently, is able to inhibit complex I by proteolysis of NDUFV2 and of NDUFB8. (note that these authors claim that it is ND6 which is cleaved but the antibody they used in the study is now known to react with NDUFB8 and not ND6).
Ref. ARRINGTON.DD., VAN VLEET.TR & SCHNELLMANN.RG. AM J Physiol. Cell. Physiol 291. C1159-71


HUNTINGTONS DISEASE AND TRAFFICKING OF MUTANT HUNTINGTIN TO MITOCHONDRIA.
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Mitochondrial disfunction has been implicated in the pathogenesis of Huntingtons disease for a number of years. In the March edition of J. Neurosci, Orr and colleagues report that accumulated (over time and age) N terminal mutants of huntingtin associate with mitochondria. The mutant protein interferes with the interaction of the organelle with microtubules along which mitochondria move. They show that the mutant protein reduces both the distribution and transport rate of mitochondria using cultured neuronal cells.
Ref. ORR.AL., LI.W., WANG.CE., RONG.J., XU.X., MASTROBERARDINO.PG., GREENAMYRE.JT & LI.XJ. J. NEUROSCI 28. 2783-92 (2008)


TRANSCRIPTION FACTORS AND NUCLEAR RECEPTORS AND THEIR INVOLVEMENT IN MITOCHONDRIAL EVENTS.
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A number of cellular transcription factors and nuclear receptors have been found in mitochondria, either temporally or as residents of the organelle. These include glucogon receptor, p53, Nur 77, ER beta CREB and even PPAR gamma2. In a recent review the diverse findings relating to the roles of these various proteins, and the dynamics of their entry into or onto mitochondria has been comprehensively reviewed. Of particular interest is the proposed dual role of p53 in regulating transcription by binding to mtDNA and its role in apoptosis via interaction with Bcl-xL/2.
PPAR gamma2 has been clamed to bind to the D-loop of mtDNA to regulate mitochondrial gene expression.
Ref. LEE.J., SHARMA.S., KIM.J., FERRANTE.RJ & RYU.H Journal of Neuroscience Research 86. 961-971 (2008)


REPAIRING H2O2 INDUCED MTDNA DAMAGE; IMPORT OF THE BASES EXCISION REPAIR ENZYME APE/REF1 TO MITOCHONDRIA.
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A somewhat older reference but of interest as the picture of ROS driven apoptosis develops, is the finding of Frossi et al that APE/Ref 1 can reside in mitochondria.
These authors used WB and confocal microscopy to show that a fraction of the protein APE/Ref1 relocalizes to mitochondria in the presence of H2O2 without inducing apoptosis.
Ref FROSSI.B., TELL.G., SPESSOTTO.P.,CLOLMBATTII.A, VITALE.G & PUCILLO.C J. Cell Physiol 193. 180-6 (2002)


LINKING BREAST CANCER WITH CONTROL OF APOPTOSIS AT THE MITOCHONDRION.
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Using cell fractionation as well as ICC studies, Tembe & Henderson have established a mitochondrial location of a fraction of BARD1, the breast cancer regulatory protein1- associated RING domain 1 protein. This protein has been shown to be mutated in a subset of breast ovarian cancers. The researchers show that mitochondrial uptake of BARD1 induced Bax oligomerization, results in apoptosis with loss of membrane potential.

Ref. TEMBE.V & HENDERSON.BR. J Biol. Chem. 282. 20513-22 (2007)


RAF-1 (ALSO CALLED RAF-C), A SERINE/THREONINE KINASE, IS TARGETED TO MITOCHONDRIA TO PREVENT STRESS MEDIATED APOPTOSIS
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Raf-1 is involved in the Ras-induced mitogen activated protein kinase pathway. This protein exists in the cytosol but has been shown to translocate to mitochondria and protect from apoptosis by binding to Bcl2 and displacing Bad. The triggers that direct Raf-1 to the mitochondrion are now being worked out. They include p21-activated kinase 1-catalyzed phosphorylation of the protein, which in turn is triggered by OX STRESS.

Ref. WU. X., CARR.HS, DAN.I., RUVOLO.PP & FROST.JA. J.Cell Biol May 8 ahead of pront 2008.

GALMICHE.A., ET.AL. J. Biol. Chem. 283. 14857-66 (2008)

JIN.S., ZHUO.Y., GUO.W & FIELS.J. J Biol.Chem 280. 24698-705 (2005)

Most interestingly the human hepatitis virus protein HBx, which plays a crucial role in viral life cycle, also causes the mitochondrial translocation of Raf-1 to mitochondria, thereby protecting the virus from cell death.

Ref. CHEN.J & SIDDIQUI A. J of Virology 81. 6757-60 (2007).


P66SHC, LIFESPAN AND MITOCHONDRIA; THE OXIDATIVE STRESS CONNECTION.
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In a series of stellar studies, Rizzuro and colleagues have established how the protein p66Shc, also called growth factor adaptor Shc 66Kd isoform, converts oxidative damage into cell death by acting as a reactive oxygen species producer within mitochondria. They have shown that protein kinase Cbeta when activated by OXSTRESS phosphorylates this protein causing translocation to mitochondria. Accumulation of the protein in the organelle depends on interaction with propyl isomerase Pin1. Inside the mitochondrion p66Shc alters Ca2+ responses, alters morphology and induces apoptosis. Further these workers have shown that p66Shc is a redox enzyme that itself generates ROS. It uses reducing equivalents delivered by cytochrome c.

Ref. GIORGIO.M. ET AL. Cell 122. 221-33 (2005)

PINTON.P & RIZZUTO.R. Cell Cycle 7. 304-8 (2008)

PINTON.P. ET AL. Science.315. 659-63 (2007)

The take home lesson from the above is that there is an as yet poorly defined trafficking of proteins into and out of mitochondria such that there is no such thing as a “static” mitochondrial protein composition. Suppose that mitochondrial proteins can migrate “en mass” for example to the plasma membrane, this would even more drastically change our perception of what proteins belong to which organelle or membrane. Beware!!!! This supposition is true as will be reviewed in a subsequent MitoNews.

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