[Targeting allotopic material to the mitochondrial compartment: new tools for better understanding mitochondrial physiology and prospect for therapy]

P Rustin — 2008-04-23T14:37:39-00:00

Médecine sciences : M/S, Vol. 23, No. 5. (May 2007), pp. 519-525.

Mitochondrial disorders can not be ignored anymore in most medical areas. They include specific and widespread organ involvement, with tissue degeneration or tumor formation, being the target of numerous viruses, e.g. the HIV. Primary or secondary actors, mitochondrial dysfunctions are also supposedly playing a role in the ageing process. Despite the progresses made in the identification of their molecular bases, nearly all remains to be done as regards therapy. Research dealing with mitochondrial physiology and pathology has a long history in France and is thus not a surprise if four French teams, coming from these fundamental domains, are involved in the challenge to find ways to fight these diseases. The directions described are working tracks which promise to be long and full of pitfalls. Being original, they share a part of risk and uncertainty, but they are also with great potential with high stakes if considering the impact of these diseases.

Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or v subunits.

C Bonnet — 2008-04-23T14:14:54-00:00

Rejuvenation research, Vol. 10, No. 2. (June 2007), pp. 127-144.

The possibility of synthesizing mitochondrial DNA (mtDNA)-coded proteins in the cytosolic compartment, called allotopic expression, provides an attractive option for genetic treatment of human diseases caused by mutations of the corresponding genes. However, it is now appreciated that the high hydrophobicity of proteins encoded by the mitochondrial genome represents a strong limitation on their mitochondrial import when translated in the cytosol. Recently, we optimized the allotopic expression of a recoded ATP6 gene in human cells, by forcing its mRNA to localize to the mitochondrial surface. In this study, we show that this approach leads to a long-lasting and complete rescue of mitochondrial dysfunction of fibroblasts harboring the neurogenic muscle weakness, ataxia and retinitis Pigmentosa T8993G ATP6 mutation or the Leber hereditary optic neuropathy G11778A ND4 mutation. The recoded ATP6 gene was associated with the cis-acting elements of SOD2, while the ND4 gene was associated with the cis-acting elements of COX10. Both ATP6 and ND4 gene products were efficiently translocated into the mitochondria and functional within their respective respiratory chain complexes. Indeed, the abilities to grow in galactose and to produce adenosine triphosphate (ATP) in vitro were both completely restored in fibroblasts allotopically expressing either ATP6 or ND4. Notably, in fibroblasts harboring the ATP6 mutation, allotopic expression of ATP6 led to the recovery of complex V enzymatic activity. Therefore, mRNA sorting to the mitochondrial surface represents a powerful strategy that could ultimately be applied in human therapy and become available for an array of devastating disorders caused by mtDNA mutations.

CiteULike: raiyars Rustin

[Targeting allotopic material to the mitochondrial compartment: new tools for better understanding mitochondrial physiology and prospect for therapy]

Allotopic mRNA localization to the mitochondrial surface rescues respiratory chain defects in fibroblasts harboring mitochondrial DNA mutations affecting complex I or v subunits.