Bacteria, yeast, worms, and flies: Exploiting simple model organisms to investigate human mitochondrial diseases

Abstract

The extensive conservation of mitochondrial structure, composition, and function across evolution offers a unique opportunity to expand our understanding of human mitochondrial biology and disease. By investigating the biology of much simpler model organisms, it is often possible to answer questions that are unreachable at the clinical level. Here, we review the relative utility of four different model organisms, namely the bacteria Escherichia coli, the yeast Saccharomyces cerevisiae, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, in studying the role of mitochondrial proteins relevant to human disease. E. coli are single cell, prokaryotic bacteria that have proven to be a useful model system in which to investigate mitochondrial respiratory chain protein structure and function. S. cerevisiae is a single-celled eukaryote that can grow equally well by mitochondrial-dependent respiration or by ethanol fermentation, a property that has proven to be a veritable boon for investigating mitochondrial functionality. C. elegans is a multi-cellular, microscopic worm that is organized into five major tissues and has proven to be a robust model animal for in vitro and in vivo studies of primary respiratory chain dysfunction and its potential therapies in humans. Studied for over a century, D. melanogaster is a classic metazoan model system offering an abundance of genetic tools and reagents that facilitates investigations of mitochondrial biology using both forward and reverse genetics. The respective strengths and limitations of each species relative to mitochondrial studies are explored. In addition, an overview is provided of major discoveries made in mitochondrial biology in each of these four model systems.

Overexpression of the Coq8 Kinase in Saccharomyces cerevisiae coq Null Mutants Allows for Accumulation of Diagnostic Intermediates of the Coenzyme Q6 Biosynthetic Pathway

“…7A), revealing that at least another biosynthetic step downstream of the O5-methylation is impaired. In agreement with these results, Coq4 was hypothesized to serve as an anchor for the Q 6 biosynthetic complex (5) and was recently proposed to bind the polyisoprenyl tail of Q 6 intermediates, therefore allowing sequential modification of the aromatic head group (29). It is of interest to note that a diploid yeast carrying a deletion of one allele of COQ4 showed a diminished Q 6 content demonstrating that wild-type level of Coq4 is crucial for the function of the Q 6 biosynthetic complex (30).…”

Identification of Coq11, a New Coenzyme Q Biosynthetic Protein in the CoQ-Synthome in Saccharomyces cerevisiae

“…Coq4 was previously hypothesized to serve as a scaffolding protein for the complex, and the crystal structure of the Coq4 homolog Alr8543 from Nostoc sp. PCC7120 revealed a bound geranylgeranyl monophosphate, suggesting that Coq4 functions to stabilize the Q biosynthetic complex through its interactions with other Coq proteins and a polyisoprenoid lipid (26,77). The crystal structure of human COQ9 was recently solved and shown to have a lipid-occupied cavity; mass spectrometry analyses of purified human COQ9 identified its association with phospholipids and Q (78).…”

Biosynthesis of coenzyme Q in eukaryotes

“…73) The direct involvement of the Alr8543 protein in CoQ synthesis has not been proven, but its cocrystallization with geranylgeranyl monophosphate supports a role as a substrate holder during CoQ synthesis. 73) In addition to the three-dimensional structures of Coq proteins and their homologs, the crystal structures of the bacterial decarboxylases UbiD (PDB ID: 4IP2) 74) and UbiX (PDB ID: 1SBZ) 75) have also been solved. A UbiX homolog named Pad1 exists in yeast, but it is not thought to be involved in CoQ synthesis.…”