Biology subjects

Tuomela, T.

Publications and source records attributed to Tuomela, T..

5 recordsLinked to original sources

bioRxiv2026

Protecting host mitochondria with vitamin B3 preserves bioenergetics and thermogenesis during antibiotic treatment

Antibiotics that target bacterial translation can also impair mitochondrial function because mitochondria retain bacterial-like ribosomes. As antibiotic resistance continues to increase and the use of several broad-spectrum antibiotics has been limited by their mitochondrial toxicity, there is a growing need to understand their off-target effects in host physiology, and to identify strategies that can mitigate antibiotic-induced mitochondrial dysfunction. We demonstrate that antibiotic chloramphenicol (CA) induces a dose-dependent reduction in mitochondrial respiration and mitochondrial thermogenesis in Drosophila S2 cells, human HEK293T cells and in developing Drosophila larvae. In vivo, CA exposure triggers female-biased aberrant innate immune activation of hosts carrying naturally occurring mitochondrial rRNA variants. Metabolomic profiling revealed alterations in vitamin B3 metabolism in Drosophila during and following CA exposure. Among the vitamin B3 vitamers examined, nicotinamide (NAM) exhibited the strongest protective effect, mitigating the CA-induced impairments in mitochondrial respiration and thermogenesis, as well as aberrant immune activation. We identify mitochondrial thermogenesis as a previously unrecognized target of antibiotic-induced mitochondrial perturbation and a sensitive marker of mitochondrial stress. Furthermore, we demonstrate that co-supplementation of CA with NAM mitigates antibiotic-induced mitochondrial toxicity through evolutionarily conserved mitochondrial pathways. Finally, we establish Drosophila as a powerful model for investigating antibiotic-induced mitochondrial dysfunction and for developing therapeutic strategies to protect host mitochondria during antibiotic treatment.

molecular biology↗

bioRxiv2025

IbinA and IbinB regulate the Toll pathway-mediated immune response in Drosophila melanogaster

To combat infection, an immune system needs to be promptly activated but tightly controlled to avoid destructive effects on host tissues. IbinA and IbinB are related short peptides with robust expression upon microbial challenge in Drosophila melanogaster. Here, we show that Ibin genes are ubiquitously present in flies of the Drosophila subgenus Sophophora, where they replace a different but probably related gene, Mibin, which is found across a much wider range of cyclorrhaphan flies. Using synthetic peptides, we did not observe any direct bactericidal or bacteriostatic activity for either IbinA or IbinB in vitro. Using mutant Drosophila lines lacking the IbinA gene, IbinB gene, or both, we examined their roles in development and during microbial infections. IbinA is expressed in early pupae, and a lack of IbinA and IbinB leads to temperature-dependent formation of melanized tissue during metamorphosis, frequently around the trachea. IbinA and IbinB have distinct effects on susceptibility to microbial infection. For example, IbinB mutant flies, as well as flies lacking both IbinA and IbinB, had improved survival when challenged with Listeria monocytogenes, an intracellular pathogen, whereas a lack of IbinA alone had no effect. RNA sequencing of wildtype and mutant flies infected with L. monocytogenes showed enhanced Toll target gene expression in flies lacking IbinB, suggesting that IbinB acts as a negative regulator of the Toll pathway. In contrast, IbinA mutants had decreased Toll target gene expression in this context. Correspondingly, IbinB mutant flies had improved and IbinA compromised survival in septic fungal infection, where the Toll pathway has a major role. Our study provides insight into the roles of IbinA and IbinB in regulation of the immune response in Drosophila. Author summaryWhile the immune systems of animals must be able to be rapidly activated, they have the potential to cause severe tissue damage when overactive. Drosophila melanogaster has proven to be a highly effective model for studying core immune system pathways, and for developing concepts in host-pathogen interactions. The main signaling pathways involved in activation of the Drosophila immune system are well described and have contributed to the discovery of homologous pathways in the mammalian immune system. Despite this, the molecular mechanisms of action of the genes expressed downstream of these pathways are generally not well characterized. Regulation of the immune response also requires further investigation. Here, we use Drosophila mutants to show roles for two short peptides, both highly expressed during infection. IbinA and IbinB regulate the humoral immune response and the melanization reaction (an insect-specific immune reaction against parasites). Flies lacking one or both of these genes mount a stronger, more effective response to some pathogenic bacteria compared to wild type flies. During development, IbinA and IbinB have tissue protective roles, with mutants showing tissue damage due to aberrant immune activation. Our results indicate that IbinA and IbinB are important regulators of the immune response with tissue protective properties.

immunology↗

bioRxiv2024

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

The role of mitochondria in both adaptive and innate immune responses is increasingly recognized, but the role of mitochondrial DNA (mtDNA) variation as an immunomodulatory factor has received less attention. One reason for this is the difficulty of separating the effect of mtDNA from that of the nuclear genome. By utilizing the fruit fly Drosophila melanogaster, a powerful model system, we created cytoplasmic hybrids, aka. cybrid lines, where unique mtDNAs (mitotypes) were introgressed into a controlled isogenic nuclear background. We harnessed a panel of cybrid lines to study the effect of mtDNA variation on humoral and cell-mediated innate immune responses. Mitotypes exhibited heterogeneity in infection outcomes upon bacterial, viral and parasitoid infections. One mitotype of note (mtKSA2) was more immunocompetent when compared to other mitotypes. We performed transcriptomic profiling of uninfected and infected flies to find the mechanistic basis of the immunocompetence of the mtKSA2 line. We found that in uninfected flies mtKSA2 caused an upregulation of oxidative phosphorylation (OXPHOS) and tricarboxylic acid cycle (TCA) related genes and a downregulation of a set of antimicrobial peptides (AMPs). Upon infection, mtKSA2 flies produced transcriptomic changes that were infection type and duration specific. When we examined immune cells (hemocytes) in mtKSA2 larvae, we noted an increase in hemocyte numbers. These hemocytes were activated in the absence of infection, increased their production of ROS, and showed evidence of increased encapsulation efficiency upon parasitoid wasp infection. Overall, our results show that mtDNA variation acts as an immunomodulatory factor in both humoral and cell-mediated innate immunity and that specific mitotypes can provide enhanced protection against various infections.

immunology↗

bioRxiv2023

Nuclear genetic background influences the phenotype of the Drosophila tko25t mitochondrial protein-synthesis mutant

The Drosophila tko25t point mutation in the gene encoding mitoribosomal protein S12 produces a complex phenotype of multiple respiratory chain deficiency, developmental delay, bang-sensitivity, impaired hearing, sugar and antibiotic sensitivity and impaired male courtship. Its phenotypic severity was previously shown to be alleviated by inbreeding, and to vary with mitochondrial genetic background. Here we show similarly profound effects conferred by nuclear genetic background. We backcrossed tko25t into each of two standard nuclear backgrounds, Oregon R and w1118, the latter used as recipient line in many transgenic applications requiring selection for the white minigene marker. In the w1118 background, tko25t flies showed a moderate developmental delay and modest bang-sensitivity. In the Oregon R background, males showed longer developmental delay and more severe bang-sensitivity, and we were initially unable to produce homozygous tko25t females in sufficient numbers to conduct a meaningful analysis. When maintained as a balanced stock over 2 years, tko25tflies in the Oregon R background showed clear phenotypic improvement though were still more severely affected than in the w1118 background. Phenotypic severity did not correlate with the expression level of the tko gene. Analysis of tko25t hybrids between the two backgrounds indicated that phenotypic severity was conferred by autosomal, X-chromosomal and parent-of-origin dependent determinants. Although some of these effects may be tko25t-specific, we recommend that, in order to minimize genetic drift and confounding background effects, the genetic background of non-lethal mutants should be controlled by regular backcrossing, even if stocks are usually maintained over a balancer chromosome.

genetics↗

bioRxiv2022

Mitochondrial perturbations enhance cell-mediated innate immunity in Drosophila

Withdrawal StatementThe authors have withdrawn version 2 of this manuscript due to the erroneous revision with a related but different manuscript, which can now be found under doi: 10.1101/2024.03.28.587162. Note that version 1 of this preprint is correct and has now been published as doi: 10.1186/s12915-024-01858-5, which should be used for citation purposes. If you have any questions, please contact the corresponding author (Tiina S. Salminen, tiina.s.salminen@tuni.fi).

immunology↗