WITHDRAWN: Mitochondrial genome variation affects humoral and cell-mediated innate immune responses and infection outcomes

Abstract

Mitochondria participate in various cellular processes including energy metabolism, apoptosis, stress responses, inflammation and immunity. While mitochondrial dysfunction contributes to many diseases, mitochondrial perturbations can also be beneficial, a phenomenon coined mitohormesis. We investigated how mitochondrial variation contributes to the heterogeneity of infection outcomes and whether moderate mitochondrial dysfunction could benefit immune-challenged individuals. We took three approaches to model variation in mitochondrial oxidative phosphorylation (OXPHOS) in Drosophila melanogaster: i) inherited natural mitochondrial DNA (mtDNA) variation present in all tissues; ii) sporadic, tissue-specific silencing of OXPHOS-related genes and iii) systemic pharmacological inhibition of OXPHOS, and studied their effects on the cell-mediated innate immune response. When perturbing mitochondrial function, we detected signs of activated cellular innate immunity without infection and upon infection the perturbation caused enhanced immune response. Our data indicate that mitochondrial dysfunction can be beneficial in immune-challenged individuals when it is mild enough and does not cause complications to the host, and ultimately causes variation in infection outcomes between individuals.Author summaryMitochondria are eukaryotic cell organelles involved in various cellular processes including metabolism and cell signaling. The role of mitochondria and the variation of mitochondrial function in immune responses have been increasingly studied across various models. Mitochondrial dysfunction, originating from either the nuclear or the mitochondrial genome, is generally considered harmful for the organism. What is not yet well understood is how immune responses are affected by mitochondrial dysfunction, for example in the context of mitochondrial disease. Here, we show that in the fruit fly Drosophila melanogaster mild systemic or immune cell -specific mitochondrial perturbations enhance the innate immune response of the host to parasitoids. Furthermore, we show that due to the mitochondrial perturbations the cell-mediated immune system of the host is activated in the absence of infection and makes the immune responses more efficient upon infection. Importantly, our results demonstrate that mitochondrial genome variation is one of the underlying factors contributing to the variation in infection outcomes among individuals. Our results therefore contribute to the understanding of innate immunity, by providing information about the genetic causes underlying the variation seen in the response to infections.

Mitochondrial background can explain variable costs of immune deployment

“…Recent work on some of the cybrids used in the present work has also found that mitochondrial variation can affect immune deployment directly, by affecting the production of ROS and the proliferation and differentiation of haemocytes during parasitoid wasp infection, particularly in lines with low mitochondrial copy number and non-synonymous substitutions in cytochrome b (OXPHOS complex II) and cytochrome c oxidase subunit 3 (COIII), such as mitotype mtKSA2 [23,50]. In addition, there is some evidence that trade-offs between immunity and fecundity are associated with disruptions in mitochondrial function [22].…”

“…Using a randomized block design, we lightly anesthetized 2-3 day old female flies (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) flies per genotype per treatment for a total of 472 flies) and pricked them in the thorax with a 5mm needle, dipped in an aliquot of heat-killed P. entomophila., or in sterile PBS to control for the effect of pricking.…”

“…In the absence of infection or immune deployment, variation in mitochondrial function has been associated with decreased lifespan, changes to locomotor activity and reproductive success, as well as developmental time and weight [17][18][19][20][21]. Thus, we may predict variation in mtDNA to generate, or contribute to, heterogeneity in the immune response [16,22,23].…”

“…In the absence of infection or immune deployment, variation in mitochondrial function has been associated with decreased lifespan, changes to locomotor activity and reproductive success, as well as developmental time and weight [17–21]. Thus, we may predict variation in mtDNA to generate, or contribute to, heterogeneity in the immune response [16,22,23]. Following this reasoning, polymorphisms that lead to changes in the efficiency of ATP production may also impact the cost of immune deployment in the form of reduced fecundity, lifespan, or other aspects of host physiology.…”

“…The copyright holder for this preprint this version posted October 6, 2023. ; https://doi.org/10.1101/2023.10.04.560830 doi: bioRxiv preprint associated with decreased lifespan, changes to locomotor activity and reproductive success, as well as developmental time and weight [17][18][19][20][21]. Thus, we may predict variation in mtDNA to generate, or contribute to, heterogeneity in the immune response [16,22,23].…”