Allotopic expression: Impossible task or a plausible strategy for the treatment of mitochondrial diseases?

Abstract

Allotopic expression refers to the functional relocation of genes from one cellular compartment to another. Here, it refers to the expression of mitochondrial genes either from the nucleus or from a cytosolic vector. It is considered a promising strategy to develop gene therapies against diseases caused by mutations in the mitochondrial genome. Nowadays, it is possible to introduce genetic material into the nuclear chromosomes and there is a good knowledge about the mechanisms of protein import into mitochondria so in principle, a single gene copy per cell would be sufficient to synthesize the necessary proteins and deliver them to all affected mitochondria. In the last 20 years allotopic expression has been tried in yeasts, plants, mammal cells and animals carrying mitochondrial diseases. Many studies published in the last 10 years suggest that allotopic expression is a successful strategy and some clinical trials using this approach are currently being carried out. Nevertheless, there is also a large number of evidence that questions the viability of allotopic expression and that proposes more stringent criteria to make sure that the allotopically-expressed proteins are actually assembled into their corresponding mitochondrial complex. In this work, we first introduce the concept of allotopic expression, then we review the most relevant data in the field and, finally, we discuss the difficulties that must be overcome before attempting gene therapies in patients with mitochondrial diseases.