Mitochondrial Diseases
Novel Genetics
November 26, 2008
Edited by Roderick Capaldi, D.Phil.
Past issues are available for review in the archives.
Table of Contents
I. INTRODUCTION
II. MORE ON COMPLEX I ASSEMBLY MUTANTS
III. THE FIRST DESCRIBED DISEASE-CAUSING NUCLEAR MUTATION IN CYTOCHROME C OXIDASE, AND MORE
IV. ANOTHER ASSEMBLY FACTOR FOR ATP SYNTHASE
V. DISEASES OF MITOCHONDRIAL DNA REPLICATION; A RAPIDLY EXPANDING AND IMPORTANT CAUSE OF OXPHOS DISEASES
VI. THE OPA SAGA
VII. HOW ARE WE GOING TO TREAT MITOCHONDRIAL DISEASES?
VIII. ONE FOR THE AGES AND THE AGED
I. INTRODUCTION
In hind-site, the genesis of MitoSciences was from the use of antibodies in my laboratory more than 25 years ago by my then post-doc Victor Darley Usmar. He used them to characterize the OXPHOS enzymes in a patient from Oregon Health Sciences University with a phenotype that had wrongly been diagnosed as muscular dystrophy. During the long gestation period before we birthed MitoSciences, the field of “Mitochondrial Diseases” has made dramatic progress; where bone fide treatments for these conditions are on the horizon. New mutations causing dysfunction of oxidative phosphorylation, and new phenotypes of these mutations, are still being reported with regularity. Below are some recent examples.
II. MORE ON COMPLEX I ASSEMBLY MUTANTS
The number of assembly factors required to put together Complex I or NADH –ubiquinone oxidoreductase continues to grow, as expected for a complex of 45 subunits along with flavin and multiple non-heme centers. Newly identified participants are C20orf7 and CIA30.
SUGIANA.C. et al. Am. J. Hum Genet 83. 468-78 (2008)
Mutation of C20orf7 disrupts Complex I assembly and causes lethal neonatal mitochondrial disease.
DUNNING.CJ. EMBO J. 26. 3227-37 (2007)
Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in it’s gene cause disease.
III. THE FIRST DESCRIBED DISEASE-CAUSING NUCLEAR MUTATION IN CYTOCHROME C OXIDASE, AND MORE
The mutated proteins causing isolated cytochrome c oxidase deficiency have up to now all been in mt-encoded subunits or in assembly factors. Recently it was reported that a mutation in subunit VIb is associated with severe infantile encephalopathy. This is the first example of a mutation in a nuclear encoded subunit of the enzyme causing disease.
MASSA.V. et al. Am. J.Hum.Genet. 82. 1281-9 (2008)
Severe infantile encephalopathy caused by a mutation in COX6B1, a nuclear-encoded subunit of cytochrome c oxidase.
A second novel mutation causing infantile encephalopathy has been reported. The gene involved is FASTKD2 the product of which is a fas-activated serine-threonine kinase domain 2, a protein associated with the mitochondrial inner membrane. Two siblings with this mutation had COX deficiency in skeletal muscle. Regular readers of MitoNews will be aware of the considerable control of cytochrome c oxidase activity provided by phosphorylation/dephosphorylation events. Could this protein be involved in COX regulation and if so is this due to modulation of activity or assembly?
GHEZZI. D. et al. Am.J.Hum.Genet. 83. 415-23 (2008)
FASTKD2 nonsense mutation in an infantile mitochondrial encephalopathy associated with cytochrome c oxidase deficiency..
IV. ANOTHER ASSEMBLY FACTOR FOR ATP SYNTHASE
In an elegant recent study, the Czech group, who have contributed a number of important recent findings on mitochondrial biogenesis, describe a new assembly factor for ATP synthase encoded by the gene TMEM70. A splicing mutant in this gene caused neonatal encephalocardiomyopathy resulting for isolated ATP synthase deficiency. Many of the key assembly factors of the repiratory chain and ATP synthase were first identified in yeast. This gene is not found in fungi, leading the authors to conclude that it is involved in an assembly step unique to the mammalian enzyme, which has subunits additional to the yeast counterpart.
CIZKOVA. A. et al. Nature Genetics 40. 1288-90 (2008)
TMEM70 mutations cause isolated ATP synthase deficiency and neonatal mitochondrial encephalocardiomyopathy.
V. DISEASES OF MITOCHONDRIAL DNA REPLICATION; A RAPIDLY EXPANDING AND IMPORTANT CAUSE OF OXPHOS DISEASES
Mutations in an expanding set of proteins involved in mitochondrial DNA replication are now well known to induce mitochondrial diseases. This includes mutations in POLG, PEO/Twinkle., ECGF1, DGUOK, TK2, MPV17 and several other genes. In an excellent recent review Copeland describes the full list of these disease-causing proteins, many of which are likely to be components of the michondrial nucleoid.
COPELAND WC. Annu. Rev.Med 59. 131-146 (2008)
Inherited mitochondrial diseases of DNA replication.
VI. THE OPA SAGA
In the last edition of MitoNews the role of OPA 1 in assembly of complexes I and V was reviewed. Two recent studies emphasize the complexity of the OPA 1 phenotype beyond the finding of optic atrophy. It is now clear that OPA1 plays an important role in stabilizing mitochondrial DNA. According to Hudson et al. there are multiple mtDNA deletions and a mosaic defect in cytochrome c oxidase in muscle. Ataxia and deafness are also part of the overall phenotype, confirming the systemic effects of mutations in this gene.
HUDSON.G. et al. Brain 131. 314-7 (2008)
Mutations of OPA 1 cause a dominant optic atrophy with external opthalmoplegia, ataxia, deafness and multiple mt DNA deletions; a novel disorder of mtDNA maintainance.
In another recent study the effect of OPA 1 mutations on mtDNA stability was identified along with the presence of a mosaic COX deficiency and the appearance of ragged red fibers in muscle tissue.
AMATI-BONNEAU.P. et al. Brain 131. 338-51 (2008)
OPA 1 mutations induce mtDNA instability and optic atrophy “plus” phenotypes.
The observations in these two papers beg the question of how a dynamin-related GTPase, already known to be involved in mitochondrial fusion, cristae organization and control of apoptosis, can at the same time stabilize the DNA. Is there interaction between OPA 1 and the mtDNA-containing nucleoid?
VII. HOW ARE WE GOING TO TREAT MITOCHONDRIAL DISEASES?
The ultimate goal of accurate diagnosis of mitochondrial diseases is to provide effective therapies for these conditions. Many avenues are being explored including replacement of mtDNA, gene therapies of the nuclear encoded OXPHOS assembly factors, as well as small molecule drug treatments. In an interesting paper Wenz et al. used a mouse model of cytochrome c oxidase deficiency and used benzafibrate, an often used therapy for lipid enzyme dysfunction, in an attempt to increase mitochondrial biogenesis via the PPAR gamma/PGC1alpha pathway. They observed the exciting result that the treatment enhanced mitochondrial proliferation with enhanced OXPHOS capacity in muscle. The overall effect was delayed onset of myopathy and a markedly prolonged lifespan of the treated animals.
WENZ.T, DIAZ.F, SPIEGELMAN.BM & MORAES CT. Cell Metab 8. 249-56 (2008)
Activation of the PPAR/PGC1alpha pathway prevents a bioenergetic deficit and improves a mitochondrial myopathy phenotype.
VIII. ONE FOR THE AGES AND THE AGED
A recent report from Du et al. will likely focus, considerably more attention than previously, on Alzheimers disease as a condition that includes and could be caused by mitochondrial dysfunction. These authors claim that interaction of cyclophilin D with the mitochondrial fraction of amyloid beta protein induces cell stress. Cyclophilin D deficiency protected neurons from A-beta and oxidative stress-induced cell death, and greatly improved learning and memory as well as synaptic function in an Alzheimers disease model mouse. Wow, we have a good mAb to cyclophilin D. I should use it to see if I can reduce my levels of this protein to prevent losing my mind. Now where is that whiskey bottle!
DU.H. et al. Nat Med. 14. 1097-105 (2008)
Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in alzheimers disease.
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