What limits the allotopic expression of nucleus-encoded mitochondrial genes? The case of the chimeric Cox3 and Atp6 genes

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• 作者：Francisco Figueroa-Martí ; nez ; Miriam Vá ; zquez-Acevedo ; Paulina Corté ; s-Herná ; ndez ; José ; J. Garcí ; a-Trejo ; Edgar Davidson ; Michael P. King ; Diego Gonzá ; lez-Halphen
• 关键词：Allotopic expression ; Human mitochondrial genes ; Chimerical proteins ; Chlamydomonas reinhardtii
• 刊名：Mitochondrion
• 出版年：2011
• 出版时间：January 2011
• 年：2011
• 卷：11
• 期：1
• 页码：147-154
• 全文大小：408 K

文摘

Allotopic expression is potentially a gene therapy for mtDNA-related diseases. Some OXPHOS proteins like ATP6 (subunit a of complex V) and COX3 (subunit III of complex IV) that are typically mtDNA-encoded, are naturally nucleus-encoded in the alga Chlamydomonas reinhardtii. The mitochondrial proteins whose genes have been relocated to the nucleus exhibit long mitochondrial targeting sequences ranging from 100 to 140 residues and a diminished overall mean hydrophobicity when compared with their mtDNA-encoded counterparts. We explored the allotopic expression of the human gene products COX3 and ATP6 that were re-designed for mitochondrial import by emulating the structural properties of the corresponding algal proteins. In vivo and in vitro data in homoplasmic human mutant cells carrying either a T8993G mutation in the mitochondrial atp6 gene or a 15 bp deletion in the mtDNA-encoded cox3 gene suggest that these human mitochondrial proteins re-designed for nuclear expression are targeted to the mitochondria, but fail to functionally integrate into their corresponding OXPHOS complexes.