Tapping In To The Breadth of Mitochondrial Research
A New Year, New Excitement
January 27, 2009
Edited by Roderick Capaldi, D.Phil.
Past issues are available for review in the archives.
Table of Contents
I. INTRODUCTION
II. PPIF GENE
III. TETHERED TO ER
IV. GDAP-1 AND COMPLEX I DEFICIENCY
V. FUNCTIONS OF MITOCHONDRIAL F1F0
VI. STAT3 IN RESPIRATION
VII. ARF: THE LAST FRONTIER?
IIX. GSK3BETA EXPRESSION
IX. HUNTINGTIN OVER-EXPRESSION
X. AMYLOID BETA OVERPRODUCTION
XI. PINK1 FUNCTION AND MITOCHONDRIAL TRAFFICKING
XII. OPPOSING EFFECTS OF SIRTUINS
XIII. VIRAL PROTEIN MOVEMENT
I. INTRODUCTION
Questions--What do anxiety, avoidance behavior and obesity have to do with each other?
What is the link between Herpes and becoming rho0?
What do Alzheimer’s, Charcot-Marie-Tooth and Huntington’s disease have to do with shape and size?
You would know the answers to these questions if you read every paper published on mitochondria each month. What! You don’t have time! O.K. I’ll make it easy for you.
II. PPIF GENE
Mice missing the Ppif gene, which encodes mitochondrial cyclophilin D, were found to be more anxious, less explorative and have an abnormal accumulation of white adipose tissue than wild type mice. (Is this why they are called wild?).
LUVISETTO S, BASSO E, PETRONILLI V, BERNARDI P & FORTE M. Neuroscience 155. 585-96 (2008)
Enhancement of anxiety, facilitation of avoidance behavior, and occurrence of adult-onset obesity in mice lacking mitochondrial cyclophilin D.
III. TETHERED TO ER
The interaction between ER and mitochondria has been known for several years and to function in Ca2+ signaling between the 2 organelles. In this study it is shown that mitofusin 2 a mitochondrial protein mutated in Charcot-Marie-Tooth type IIa is enriched in the ER- mitochondrial interface. Down regulation of mitofusin 2 disrupts the interaction between the 2 organelles and reduces the efficiency of mitochondrial Ca2+ uptake.
DE BRITO OM & SCORRANO L. Nature 456. 605-10 (2008)
Mitofusin 2 tethers endoplasmic reticulum to mitochondria.
IV. GDAP-1 AND COMPLEX I DEFICIENCY
A deficiency in Ganglioside-induced Differentiation Associated Protein (GDAP1), an outer mitochondrial membrane protein is associated with a second form of Charcot-Marie-Tooth disease (type IVa). Fibroblasts from patients with a mutation in the gene for this protein had only 60% of normal complex I activity, wider (33%) tubular mitochondria and 20% greater mitochondrial mass.
CASSEREAU J et al. Neurogenetics in press. (2008)
Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K).
V. FUNCTIONS OF MITOCHONDRIAL F1F0
The mitochondrial F1F0 plays many more functions than just a generator of ATP, or in the reverse direction as an ATPase and generator of the mitochondrial membrane potential when respiration is blocked. It is on the plasma membrane of cells where it acts as an angiostatin receptor, a HDL receptor and more. Release of CF6 from endothelial cells is involved in hypertension. The list of ancillary functions continues to grow. In the study it is shown that (immediate early response gene X-1 (IEX-1) targets IF1, the ATP synthase inhibitor protein, for degradation, thereby increasing ATPase activity and reducing free radical production.
Shen L, Zhi L, Hu W, Wu MX. Cell Death Differ. Dec 19. (2008)
IEX-1 targets mitochondrial F1Fo-ATPase inhibitor for degradation.
VI. STAT3 IN RESPIRATION
There is a growing list of transcription factors that can move into and out of mitochondria such as estrogen receptor and p53. Now add Stat3. The authors provide evidence of the presence of Stat3 in mitochondria in cultured cells as well as in liver and heart. In Stat3 negative cells the activities of complexes I and II were greatly reduced, indicating that the protein is important for optimal function of the electron transfer chain.
WEGRZYN J et. al. Science Jan 9 (2009) pub online.
Function of Mitochondrial Stat3 in Cellular Respiration.
VII. ARF: THE LAST FRONTIER?
Another protein that moves into mitochondria is ARF a tumor suppress protein, which controls cell cycle progression through activation of p53. The above paper shows that mitochondrial ARF interacts with p32/CIQBP to induce apoptosis.
Itahana K, Clegg HV, Zhang Y. Cell cycle 7. 3641-6 (2008)
ARF in the mitochondria: the last frontier?
IIX. GSK3BETA EXPRESSION
Along with transcription factors, mitochondria also take up kinases that control energy metabolism. In this study GSK3 beta expressed in mitochondria enhanced apoptosis by MPP+ and significantly reduced complex I activity and ATP production. Free radical production was also increased along with perturbation of the organelle.
King TD, Clodfelder-Miller B, Barksdale KA, Bijur GN. Neurotox Res 14. 367-82 (2008)
Unregulated mitochondrial GSK3beta activity results in NADH:ubiquinone oxidoreductase deficiency.
IX. HUNTINGTIN OVER-EXPRESSION
Huntington’s disease, along with Freidriech’s Ataxia and several others, is caused by CAG trinucleotide expansion in a protein gene, in this case in huntingtin. In this study the mitochondrial properties of HeLa cells was measured after transfection with GFP-tagged forms of huntingtin containing from 17 to over 130 repeats. The more repeats there were in the protein, the more the mitochondria had increased levels of oxidative stress, increased fragmentation, reduced movement and impaired fusion.
Wang et. al. Hum Mol Genet Nov 27 ahead of print (2008)
Effects of overexpression of Huntingtin proteins on mitochondrial integrity.
X. AMYLOID BETA OVERPRODUCTION
Regular readers of MitoNews have been directed to papers showing uptake of amyloid protein beta by mitochondria, and interaction of this with aldehyde dehydrogenase, and cytochrome c oxidase. This paper shows that cells over-expressing the protein displayed altered morphology and distribution. In the process the levels of dynamin-like 1 protein and OPA1 were decreased while the levels of Fis 1 were greatly increased.
Wang X et. al. Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23.
Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins.
XI. PINK1 FUNCTION AND MITOCHONDRIAL TRAFFICKING
Pink 1 is a mitochondrially-located kinase, whose mutation leads to early onset Parkinson’s disease. Following the pattern connecting many of the papers listed in this MitoNews, evidence is presented that Pink 1 function is connected to mitochondrial morphology. A complex between the GTPase Miro, Pink 1 and an adaptor protein Milton is reported along with interaction between Pink1 and Mitofilin. The connection then is that both Miro and Milton are involved in trafficking mitochondria along microtubules.
Weihofen A et. al. Biochemistry. Jan 20 (2009) pub before in print.
Pink1 forms a multi-protein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking.
XII. OPPOSING EFFECTS OF SIRTUINS
In this study the authors examined the effect of SIRT 1 through 7 in cerebellar granule neurons. They find that SIRT 1 protects neurons from apoptosis induced by low potassium by a mechanism that does not involve deacetylase activity. SIRT 2,3 and 6 each induce apotosis when over-expressed. Also, SIRT5 can localize to mitochondria to promote cell death.
Pfister JA et. al. PLoS ONE 3 e4090 (2008)
Opposing effects of sirtuins on neuronal survival: SIRT1-mediated neuroprotection is independent of its deacetylase activity.
XIII. VIRAL PROTEIN MOVEMENT
These two papers add to the evidence that viruses move proteins to mitochondria to affect various organellar functions including blocking apoptosis. These authors identify the targeting of one protein of Herpes simplex with a mitochondrial location and also report that the organellar infection leads to a rapid and complete degredation of host cell mitochondrial DNA.
Saffran HA et. al. EMBO REP 8. 188-93 (2007)
Herpes simplex virus eliminates host mitochondrial DNA.
Corcoran JA et. al. J Virol (2009) online ahead of print.
Herpes simplex virus UL12.5 targets mitochondria through a mitochondrial localization sequence proximal to the N-terminus.
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New Publications By The MitoSciences Team
"Relationships among molecular genetic and respiratory properties of Parkinson's disease cybrid cells show similarities to Parkinson's brain tissues." Biochim Biophys Acta. 2009 Jan;1792(1):68-74. Epub 2008 Oct 10.
"Screening for the metabolic basis of neurodegeneration: developing a focused proteomic approach." Ann N Y Acad Sci. 2008 Dec;1147:348-57.
"Isolated deficiencies of OXPHOS complexes I and IV are identified accurately and quickly by simple enzyme activity immunocapture assays." Biochim Biophys Acta. 2008 Nov 10.
"Mitochondrial oxidative phosphorylation protein levels in peripheral blood mononuclear cells correlate with levels in subcutaneous adipose tissue within samples differing by HIV and lipoatrophy status." AIDS Research and Human Retroviruses. October 1, 2008, 24(10): 1255-1262.
"Monitoring oxidative and nitrative modification of cellular proteins; a paradigm for identifying key disease related markers of oxidative stress." Advanced Drug Delivery Reviews. October-November 2008, Pages 1497-1503.
"Lateral-flow immunoassay for the frataxin protein in Friedreich's ataxia patients and carriers." Molecular Genetics and Metabolism. August 2008, Pages 491-497.
"Mitochondrial oxidative phosphorylation protein levels in peripheral blood mononuclear cells correlate with levels in subcutaneous adipose tissue within samples differing by HIV and lipoatrophy status." AIDS Research and Human Retroviruses. October 1, 24(10): 1255-1262.
"Monitoring oxidative and nitrative modification of cellular proteins; a paradigm for identifying key disease related markers of oxidative stress." Advanced Drug Delivery Reviews, Volume 60, Issues 13-14, October-November 2008, Pages 1497-1503.
"Lateral-flow immunoassay for the frataxin protein in Friedreich's ataxia patients and carriers." Molecular Genetics and Metabolism,
Volume 94, Issue 4, August 2008, Pages 491-497.
"In Vitro Assessment of Mitochondrial Dysfunction and Cytotoxicity of Nefazodone, Trazodone and Buspirone." Tox Sci. doi:10.1093/toxsci/kfn056.
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