Mitochondrial medicine: to a new era of gene therapy for mitochondrial DNA mutations

Abstract

Mitochondrial disorders can no longer be ignored in most medical disciplines. Such disorders include specific and widespread organ involvement, with tissue degeneration or tumor formation. Primary or secondary actors, mitochondrial dysfunctions also play a role in the aging process. Despite progresses made in identification of their molecular bases, nearly everything remains to be done as regards therapy. Research dealing with mitochondrial physiology and pathology has >20 years of history around the world. We are involved, as are many other laboratories, in the challenge of finding ways to fight these diseases. However, our main limitation is the scarcety of animal models required for both understanding the molecular mechanisms underlying the diseases and evaluating therapeutic strategies. This is especially true for diseases due to mutations in mitochondrial DNA (mtDNA), since an authentic genetic model of mtDNA mutations is technically a very difficult task due to both the inability of manipulating the mitochondrial genome of living mammalian cells and to its multicopy nature. This has led researchers in the field to consider the prospect of gene therapy approaches that can roughly be divided into three groups: (1) import of wild-type copies or relevant sections of DNA or RNA into mitochondria, (2) manipulation of mitochondrial genetic content, and (3) rescue of a defect by expression of an engineered gene product from the nucleus (allotopic or xenotropic expression). We briefly introduce these concepts and indicate where promising progress has been made in the last decade.

Ciona intestinalis NADH dehydrogenase NDX confers stress-resistance and extended lifespan on Drosophila

“…In mammals (e.g. bovine), this complex consists of 45 subunits encoded by separate genes, seven of which are in the mitochondrial genome [1][2][3]. Mutations in these genes lead to diverse pathologies affecting the central nervous system, sensory organs, and skeletal and heart muscle, which may manifest at any stage of life.…”

Consequences of zygote injection and germline transfer of mutant human mitochondrial DNA in mice

“…However, an animal model confirming the pathogenicity of the G11778A mutation has never been developed. Moreover, therapies for disorders caused by mutated mtDNA are inadequate, in large part because of the absence of animal models with mutated mtDNA and with the same genotype and phenotype as the human disorder that would help uncover the pathogenesis of disease and test potential avenues for treatment (11)(12)(13). Current procedures for the introduction of artificially mutagenized mtDNA into mitochondria have generated optic neuropathy in mice with a gene [ND6 G14600A (P25L)] that, when homoplasmic, is responsible for Leigh syndrome in humans (14).…”

Mitochondrial Genetic Manipulation

“…The counterpart is that a number of these approaches so far remained confined to one laboratory, and some are openly controversial. Mitochondrial medicine is on the way (e.g., Cwerman-Thibault et al 2011), but the current challenge is to validate independently confirmed and generally accepted biotechnological tools (Lightowlers 2011). The stake is worth the effort.…”