Presentation
Clinical Research Group 1 « Mitochondrial diseases and mtDNA instability »
Pr Véronique PAQUIS-FLUCKLINGER, PU-PH, Team Leader
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Summary Despite the majority of mitochondrial respiratory chain (MRC) components are nuclear-encoded, each mitochondrion contains 2 to 10 copies of a small (16569bp), circular, double-stranded DNA molecule. Mitochondrial diseases can be secondary to mutations either in the mitochondrial or in the nuclear genome and are responsible for a large variety of clinical syndromes. In the team, we are studying mitochondrial disorders and mainly those associated with mtDNA instability. We have shown that the origin of the instability may be exceptionally dependent on mtDNA itself by describing, for the first time, an unstable mutation in a mitochondrial gene encoding a complex I subunit (MT-ND6), which is responsible for Maternally Inherited Diabetes and Deafness (MIDD) (Bannwarth et al., 2011). Nevertheless, in most cases, human diseases associated with loss of mtDNA copies (depletion) or accumulation of multiple mtDNA deletions have an autosomal mode of inheritance, indicating that a defect in a nuclear gene is responsible for mtDNA instability. Indeed, the factors involved in mtDNA maintenance are encoded by nuclear genes and imported into mitochondria. Mutations in any of these genes may disturb mtDNA maintenance mechanisms and cause either quantitative or qualitative mtDNA molecular lesions. A few number of defective genes has been identified but, in most patients, genes and molecular mechanisms responsible for mtDNA alterations remain unknown.
Premature aging in mice accumulating mtDNA mutations due to genetic inactivation of the mitochondrial polymerase proof reading activity (Mutator mice) From Aleksandra Trifunovic et al.Premature ageing in mice expressing defective mitochondrial DNA polymerase.Nature 429, 417-423 (2004) |
 Mitochondrial myopathy with mtDNA instability A-B. Histopathology with Gomori modified trichrome (A) showing RRFs and COX/SDH stain (B) revealing COX-deficient fibres, which are recognized by the prevalent blue stain. C. Ultrastructure of skeletal muscle showing accumulation of lipid droplets and abnormal enlarged mitochondria with paracristallin inclusions. Original magnification: x12000. D-E. Molecular analysis. Long-range PCR (D) and Southern blot (E) analysis revealing multiple deletion bands in addition to wild-type fragments. M: lambda HindIII/EcoRI (left) and 1Kb DNA ladder (right). C: control individual. P: patient. From Rouzier et al., Brain, 2012
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Research Project
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Research Project |
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Our aim is to identify new genes and mechanisms involved in mtDNA instability disorders by 2 different approaches: (i) the study of patients and families affected by mitochondrial disorders associated with multiple mtDNA deletions or depletion and, (ii) the analysis of candidate genes encoding proteins involved in mtDNA maintenance in mouse model system
This work is made in direct collaboration with the Department of Medical Genetics and the Reference Centre for Mitochondrial Diseases (CHU of Nice, Archet 2 hospital), both managed by Véronique Paquis-Flucklinger. In this Centre, we collected a large series of patients with MRC defects. This situation allows a direct link between basic and medical research. The research team benefits from the collection of patients and the expertise of referring clinicians. The recent identification of MFN2, involved in the mitochondrial fusion, as a new gene associated with "mtDNA breakage syndrome" (Rouzier et al., 2012), illustrates the value of this collaboration.
This is another approach used in the laboratory. For example, we are currently studying a protein involved in mtDNA metabolism through the analysis of KO mice. The animals developed a mitochondrial myopathy after 1 year of age with respiratory chain deficiency and accumulation of mtDNA deletions. KO mice exhibited a significantly lower daily running distance compared to wild-type animals, indicating muscle weakness. We find that the mitochondrial isoform encoded by this gene, generated via downstream alternative translation initiation (dATI), was present inside mitochondria and bound to mtDNA in vivo. Furthermore, gene inactivation caused a deficiency in repair of oxidative mitochondrial DNA damage, thus confirming the role of this protein in mtDNA maintenance. These results open new avenues for the exploration of patients with mtDNA instability disorders and for the study of thid protein that plays a critical role in the maintenance of mtDNA stability, possibly preventing age-associated accumulation of mtDNA mutations. |
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Research Group
Research Group
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AIT EL MKADEM-SAADI Samira, IR CHU
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