Lethal Interaction of Nuclear and Mitochondrial Genotypes inDrosophila melanogaster

Abstract

Drosophila melanogaster , like most animal species, displays considerable genetic variation in both nuclear and mitochondrial DNA (mtDNA). Here we tested whether any of four natural mtDNA variants was able to modify the effect of the phenotypically mild, nuclear tko 25t mutation, affecting mitochondrial protein synthesis. When combined with tko 25t , the mtDNA from wild strain KSA2 produced pupal lethality, accompanied by the presence of melanotic nodules in L3 larvae. KSA2 mtDNA, which carries a substitution at a conserved residue of cytochrome b that is predicted to be involved in subunit interactions within respiratory complex III, conferred drastically decreased respiratory capacity and complex III activity in the tko 25t but not a wild-type nuclear background. The complex III inhibitor antimycin A was able to phenocopy effects of the tko 25t mutation in the KSA2 mtDNA background. This is the first report of a lethal, nuclear-mitochondrial interaction within a metazoan species, representing a paradigm for understanding genetic interactions between nuclear and mitochondrial genotype relevant to human health and disease.

WITHDRAWN: Mitochondrial genome variation affects humoral and cell-mediated innate immune responses and infection outcomes

“…However, knocking down the OXPHOS cI-cV specific genes from the hemocytes did not affect the development rate or viability when compared to controls. Given the central role of hemocytes in the cell-mediated innate immunity, the observation of melanotic nodules in the mtKSA2 variant [23] and our finding that mtKSA2 had more hemocytes and potential hemocyte activation in the absence of infection (Fig 2A-A'), we focused our studies on larval hemocytes and the effect of decreased OXPHOS function in hemocytes on cell-mediated innate immune response.…”

Drosophila as a Model System to Investigate the Effects of Mitochondrial Variation on Innate Immunity

“…Formation of melanotic nodules is considered a sign of activated cell mediated innate immunity, and it usually involves the proliferation and aggregation of hemocytes, Drosophila blood cells (56). Furthermore, CYTB mutation bearing mitotype in a tko 25t nuclear background caused 100% pupal lethality, which is a first report of synthetic lethality between nuclear-mitochondrial interaction within a metazoan species (55).…”

“…In Drosophila, a mito-nuclear incompatibility resulted in energetically compromised flies that were more susceptible to infection by a bacterial pathogen (54). Salminen et al, identified an OXPHOS Complex III mutation D 21 N in D. melanogaster mitochondrial CYTB gene, that was shown to cause larval stage melanotic nodules in a healthy nuclear background (6%) and a significant increase (56%) of melanotic nodules when the mitotype was introgressed into a tko 25t nuclear background (55). Formation of melanotic nodules is considered a sign of activated cell mediated innate immunity, and it usually involves the proliferation and aggregation of hemocytes, Drosophila blood cells (56).…”

“…However, even after multiple generations of backcrossing, some loci are likely to never recombine if they result in strongly deleterious or even lethal phenotypes, and such loci will remain a source of residual heterozygosity regardless of the number of generations of backcrossing. This method has been used in D. melanogaster experiments to study the effect of mito-nuclear interactions on mtDNA copy number, respiration, development time and weight (40) as well as in experiments where the effect of mtDNA variants on mitochondrial diseases has been assayed in combination with the balancer chromosome method (55,98). The method has been also employed in other insect species where the use of balancer chromosomes is not possible, where the effect of mito-nuclear crosstalk has been studied on traits such as metabolism and aging in D. simulans (99), metabolic rate in Drosophila subobscura (100), and personality (101), bioenergetics, aging, life history traits (102), and male mating costs (47) in seed beetles.…”

Mitonuclear interactions affect locomotor activity and sleep in Drosophila melanogaster

“…Consequently, precise and synchronised coordination between the two genomes is required for proper assembly and function of the components of the electron transport chain and mitochondrial functions. Disruptions to this system -by mutations in the mitochondrial or nuclear counterparts -can have consequences to a wide-range of life-history phenotypes (10), and in severe cases leads to mitochondrial disease (11)(12)(13)(14)(15).…”