A Cytoplasmic Suppressor of a Nuclear Mutation Affecting Mitochondrial Functions inDrosophila

Abstract

Phenotypes relevant to oxidative phosphorylation (OXPHOS) in eukaryotes are jointly determined by nuclear and mitochondrial DNA (mtDNA). Thus, in humans, the variable clinical presentations of mitochondrial disease patients bearing the same primary mutation, whether in nuclear or mitochondrial DNA, have been attributed to putative genetic determinants carried in the “other” genome, though their identity and the molecular mechanism(s) by which they might act remain elusive. Here we demonstrate cytoplasmic suppression of the mitochondrial disease-like phenotype of the Drosophila melanogaster nuclear mutant tko25t, which includes developmental delay, seizure sensitivity, and defective male courtship. The tko25t strain carries a mutation in a mitoribosomal protein gene, causing OXPHOS deficiency due to defective intramitochondrial protein synthesis. Phenotypic suppression was associated with increased mtDNA copy number and increased mitochondrial biogenesis, as measured by the expression levels of porin voltage dependent anion channel and Spargel (PGC1α). Ubiquitous overexpression of Spargel in tko25t flies phenocopied the suppressor, identifying it as a key mechanistic target thereof. Suppressor-strain mtDNAs differed from related nonsuppressor strain mtDNAs by several coding-region polymorphisms and by length and sequence variation in the noncoding region (NCR), in which the origin of mtDNA replication is located. Cytoplasm from four of five originally Wolbachia-infected strains showed the same suppressor effect, whereas that from neither of two uninfected strains did so, suggesting that the stress of chronic Wolbachia infection may provide evolutionary selection for improved mitochondrial fitness under metabolic stress. Our findings provide a paradigm for understanding the role of mtDNA genotype in human disease.

Mito-Nuclear Interactions Affecting Lifespan and Neurodegeneration in aDrosophilaModel of Leigh Syndrome

“…adenine translocator-1 deficiency and the clinical expression of Leber's hereditary optic neuropathy (Hudson et al 2007;Strauss et al 2013). Finally, in Drosophila, mitochondrial disease-like phenotypes can be suppressed by a maternally inherited factor, likely mitochondria (Chen et al 2012).…”

“…In various diseases modeled by cultured cell lines established by transmitochondrial cytoplasmic hybrid production, mtDNA haplogroups have been associated with changes in mtDNA copy number (Wallace 2015). And finally, in Drosophila, cytoplasmic suppression of a mutant phenotype caused by mutation in a nuclear encoded mitochondrial protein was correlated with increased mtDNA copy number (Chen et al 2012). To determine whether the mitochondrial backgrounds that modify ND23 mutant phenotypes are correlated with mtDNA copy number differences, we measured mtDNA copy number in (♀)ND23 G14097 /ND23 60114 and (♀)ND23 60114 /ND23 G14097 flies.…”

“…Work in Drosophila, however, has provided important support for this hypothesis. In Drosophila, the mitochondrial disease-like phenotype caused by a mutation in technical knockout (a nuclear gene encoding a mito-ribosomal protein) can be suppressed by a cytoplasmic factor that increases mtDNA copy number (Chen et al 2012). Although this factor appears to be mitochondrial in nature, mtDNA changes that were present in all suppressor strains and absent from all nonsuppressor strains (or vice versa) could not be identified.…”

Selfish Drive Can Trump Function When Animal Mitochondrial Genomes Compete

“…The D. melanogaster version is AT-rich (> 90%) and large (~4.6 kb), and is mainly (> 90%) composed of five tandem type I repeats and four tandem type II 22 (Supplementary Figure 2a). Within D. melanogaster, this region exhibits frequent nucleotide and length polymorphisms [23][24][25] (e.g. Supplementary Figure 2a & b), and the divergence is more extensive in other Drosophila species 26,27 (e.g.…”

Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate inDrosophilalarvae

“…Bang-sensitivity is reported as a feature of mutants in two other genes for core functions of mitochondria, namely sesB (adenine nucleotide translocase) [46] and kdn (citrate synthase) [47]. These mutants, as well as tko 25t , show ATP depletion [47][48][49]. Global tko knockdown was here shown to phenocopy both the developmental delay ( Figure 3) and bangsensitivity ( Figure 4) of the original tko 25t mutant, supporting the view that tko 25t is a simple hypomorph.…”