Why mitochondria need a genome revisited

Abstract

In this paper, we experimentally address the debate about why functional transfer of mitochondrial genes to the nucleus has been halted in some organismal groups and why cytosolic expression of mitochondrial proteins has proven remarkably difficult. By expressing all 13 human mitochondrial-encoded genes with strong mitochondrial-targeting sequences in the cytosol of human cells, we show that all proteins, except ATP8, are transported to the endoplasmic reticulum (ER). These results confirm and extend previous findings based on three mitochondrial genes lacking mitochondrial-targeting sequences that also were relocated to the ER during cytosolic expression. We conclude that subcellular protein targeting constitutes a major barrier to functional transfer of mitochondrial genes to the nuclear genome.

The Origin and Diversification of Mitochondria

“…Without a rapid regulatory response to the redox state of a particular organelle, the ETC would cease to function efficiently and generate damaging reactive oxygen species, providing a selective advantage for retention of the genes on the organellar chromosome. A second explanation [127] holds that many of the proteins that are frequently retained on organellar genomes cannot be expressed in the cytosol because they are large hydrophobic proteins with multiple transmembrane domains that would preferentially be mistargeted to the ER. Specifically, when 12 ETC components frequently encoded on mtDNA are expressed in the nucleus, they have been shown to localize to the ER in human cells, even when fused with a canonical mitochondrial targeting peptide [127].…”

“…A second explanation [127] holds that many of the proteins that are frequently retained on organellar genomes cannot be expressed in the cytosol because they are large hydrophobic proteins with multiple transmembrane domains that would preferentially be mistargeted to the ER. Specifically, when 12 ETC components frequently encoded on mtDNA are expressed in the nucleus, they have been shown to localize to the ER in human cells, even when fused with a canonical mitochondrial targeting peptide [127]. Mislocalization provides a likely barrier to their evolutionary transfer to the nucleus.…”

Intercompartmental Piecewise Gene Transfer

“…According to this hypothesis, hydrophobic regions, including transmembrane helices of proteins encoded by several mitochondrial genes, might prohibit those proteins from being effectively targeted back to mitochondria if they are translated on cytosolic ribosomes. They might be mistargeted to the endoplasmic reticulum (ER) [ 92 , 97 ], or they might be incorrectly translocated and assembled in the mitochondrial inner membrane [ 93 , 94 ]. This hypothesis was originally based on the comparison of the hydrophobicity of mitochondrial proteins encoded by nuclear and mitochondrial gene homologs showing that nuclear genome-encoded proteins were less hydrophobic than their mtDNA-encoded counterparts [ 76 , 92 , 98 , 99 ].…”

“…Nuclear genomes of plants have higher mutation rates compared to organellar genomes, and there are known cases of cox2 wherein the gene is not only expressed from both nuclear and mitochondrial genomes, but also has been apparently lost from the nucleus in some groups following the establishment of its expression there [ 98 ]. In addition, interactions between mitochondrial and cytosolic proteins may interfere with the import of nucleus-encoded mitochondrial proteins [ 97 ]. The hydrophobicity hypothesis alone cannot, for instance, explain why the rps10 gene, encoding a relatively hydrophilic ribosomal protein, has been functionally transferred to the nuclear genome late in the mitochondrial evolution of angiosperms but not in other plants, even though it can be imported without mitochondrial targeting presequence [ 77 ].…”

Mitochondrial versus nuclear gene expression and membrane protein assembly: the case of subunit 2 of yeast cytochromecoxidase

“…The evolutionary constraints that maintain this genetic material in mitochondria have been addressed previously ( Adams and Palmer, 2003 ; Allen, 2015 ; Björkholm et al. , 2015 , 2017 ; Johnston and Williams, 2016 ). The hydrophobic nature of the proteins encoded in this genome plays a central role in gene retention ( Claros et al.…”