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Selfish mitochondria exploit nutrient status across different levels of selection

Bryan L. Gitschlag, Ann T. Tate, Maulik R. Patel

Preprint posted on 31 January 2020 https://www.biorxiv.org/content/10.1101/2020.01.30.927202v1

Cheater, cheater, pumpkin eater: How selfish mitochondrial DNA uses nutrient abundance and signaling to proliferate

Selected by Maiko Kitaoka

Background: An evolutionary paradox

Most people think about “survival of the fittest” when considering evolutionary selection, where bad or harmful traits are eventually selected out of the population. But some processes in biology encounter selfish “cheater” elements, which hijack this evolutionary process to maintain their continued propagation. In particular, they benefit from cooperative contributions of other processes without reciprocating. Many selfish elements are thought to use resource availability, such as when cancer cells exploit available growth factors and nutrients to proliferate.

In their recent work, Gitschlag et al dive into the intricacies of mitochondrial DNA (mtDNA) selection. The thousands of mitochondria in every cell each contain multiple copies of mtDNA. This network of organelles must cooperate to provide the cell with enough energy, while the cell’s nuclear genome reciprocates by supplying the replication machinery and building blocks necessary to maintain and replicate mtDNA. However, cells are often heteroplasmic, where more than one type of mtDNA is present, some of which can be deleterious to the cell. Selfish mtDNA is deleterious to the host’s fitness but can still propagate successfully. Here, the authors investigate selfish mtDNA selection, both at the population level as well as within an organism, uncovering an intriguing role for nutrient availability and specific signaling pathways.

Key findings: How does nutrient availability influence natural selection on selfish mitochondrial DNA?

Gitschlag et al tackled this question by using mutant C. elegans worms that lack a large portion of the mitochondrial DNA genome (ΔmtDNA), thus disrupting its function. As one might expect, increased ΔmtDNA compromised the host worm’s fitness, in terms of both oxygen consumption and production of viable progeny. In a competition assay where worms with and without ΔmtDNA were grown on the same plate, the worms with ΔmtDNA were selected against, becoming less frequent in the population. Adult worms generally gave rise to embryos that initially had less ΔmtDNA, but ΔmtDNA continued to proliferate throughout the worms’ development until the progeny had higher amounts than the parents. So, while ΔmtDNA is selected against in a population and in the female germline, this negative selection is not maintained within each organism’s lifespan. The authors combined their experimental data with mathematical modeling to demonstrate the balance between sub-organismal and organismal selection based on mtDNA frequency, returning to these models later in their work as they added more variables, such as nutrient availability.

Placing wildtype and ΔmtDNA carriers together on the same plate demonstrates the population-level selection against ΔmtDNA. From Figure 2.

 

To make a connection between ΔmtDNA and nutrient availability, the authors placed worms on a restricted diet. This abolished the developmental increase in ΔmtDNA, suggesting that ΔmtDNA somehow exploits nutrient abundance to proliferate. When the authors targeted insulin signaling, a known nutrient-dependent growth pathway, worms without the insulin receptor, DAF-2, also had no developmental increase in ΔmtDNA even on a regular diet. Conversely, animals with wildtype DAF-2 demonstrated a large increase in ΔmtDNA. Co-deletion with a downstream transcription factor, FoxO/DAF-16, rescued ΔmtDNA proliferation, indicating that FoxO/DAF-16 plays a role in this process as well.

The authors dissected this pathway to determine how insulin signaling, FoxO, and nutrients mediated ΔmtDNA frequency and total mtDNA copy number. Adapted from Figure 4.

 

The authors also noticed that total mtDNA copy number increased in worms with the wildtype nuclear background, which was entirely due to ΔmtDNA proliferation. This copy number increase disappeared in daf-2 mutants and reappeared in co-deleted worms, demonstrating that insulin signaling inhibits FoxO/DAF-16 to allow high mtDNA copy number, and subsequently allows ΔmtDNA proliferation. They next sought to uncover how DAF-16 might suppress mtDNA copy number when insulin signaling is lost. They found that mitochondrial quantity and mtDNA copy number were always proportional to gonad size, but mitochondrial elimination pathways and cellular apoptosis were not involved. Thus, FoxO/DAF-16 suppresses germline growth and mtDNA biogenesis.

Amazingly, the authors discovered that diet restriction and FoxO/DAF-16 independently limit mtDNA copy number: on a normal diet, ΔmtDNA frequency increased only when FoxO/DAF-16 was unaffected. In addition, mtDNA copy number increased without an accompanying ΔmtDNA increase in daf-16 mutants, even on an unrestricted diet.

FoxO/DAF-16 clearly has two opposing roles – firstly, when insulin signaling is lost, FoxO/DAF-16 suppresses germline development and mtDNA proliferation, limiting the space for ΔmtDNA to increase. But when nutrients are abundant, FoxO/DAF-16 is required to allow ΔmtDNA to proliferate preferentially, demonstrating that both nutrient abundance and FoxO/DAF-16 are necessary, but neither is sufficient by itself to confer ΔmtDNA’s selection advantage. At the organismal level, selection against ∆mtDNA was not affected across populations with wildtype FoxO/DAF-16 that were maintained on a restricted diet. But selection against ΔmtDNA was accelerated in daf-16 mutant populations on a restricted diet, demonstrating the strongest selection against ΔmtDNA when the ability to cope with food scarcity is compromised. Gitschlag et al have demonstrated how cheating elements can take advantage of available resources, combining different levels of evolutionary selection to shape a population.

Questions for the authors

Is a specific genetic element mediating selfishness? Or does any mtDNA deletion or mutation lead to selfishness?

Does the type of nutrient and/or dietary composition matter? I’m unsure about specifics of C. elegans diets, but if the diet had less protein, or increased carbohydrates, etc – how might this affect ΔmtDNA proliferation? Are specific bacteria/food sources better (or worse) at mediating this proliferation and why?

Relatedly, do other growth factors have similar effects on ΔmtDNA proliferation?

Your work specifically addresses mtDNA in the germline, but is it germline-specific? Do somatic mitochondria follow the same selection patterns of ΔmtDNA proliferation?

Tags: biological cheaters, cheating, cooperation, evolution, fitness, insulin signaling, mitochondria, mitochondrial dna, nematodes, nutrient abundance, selfish elements, worms

Posted on: 13 April 2020 , updated on: 14 April 2020

doi: https://doi.org/10.1242/prelights.8954

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Author's response

Bryan L. Gitschlag, Maulik R. Patel shared

Questions for the authors

Is a specific genetic element mediating selfishness? Or does any mtDNA deletion or mutation lead to selfishness?

BG and MP: Broadly speaking, “selfishness” could apply to any genetic element whose replicative fitness is decoupled from the fitness of its host. Cheating has a narrower definition that involves receiving (but not providing) a beneficial contribution in a cooperative relationship. Not all mtDNA mutations lead to this type of selfishness. However, whenever we identify a mutant mtDNA variant that undergoes positive selection within a host, and simultaneously negative selection at the level of host fitness, that is a classic indicator of a cheating element. The mtDNA mutant is somehow receiving the benefit of replication machinery (supplied by the host genome) and this occurs in the absence of making a positive contribution to host fitness. For all we know, we are merely seeing the tip of the iceberg when it comes to understanding the mechanistic causes for this phenomenon, and it may be a diversity of separate contributing factors.

 

Does the type of nutrient and/or dietary composition matter? I’m unsure about specifics of C. elegans diets, but if the diet had less protein, or increased carbohydrates, etc – how might this affect ΔmtDNA proliferation? Are specific bacteria/food sources better (or worse) at mediating this proliferation and why?

BG and MP: There is some evidence from mammalian cell culture studies that the type of nutrient affects the sub-cellular selection for one mtDNA genotype over another. The conventional wisdom goes like this: since glycolysis also produces ATP, if you force the cell to bypass glycolysis (by only providing nutrients that can yield ATP via mitochondrial respiration) then you can bias sub-cellular selection in favor of healthier, wildtype genomes. And indeed there are strains of dietary bacteria that differ from one another in their composition in macronutrients. The dietary bacteria used in our study, the OP50 strain of E. coli, is commonly regarded as a “high fat” diet, but we do not know how this food source compares to other bacterial strains with respect to its impact on mitochondrial heteroplasmy dynamics. One of the problems is the diversity of nutrients in any given live food source. If we observe that ∆mtDNA persists at different sub-organismal frequency depending on the food strain, that would be exciting, but dissecting the biochemical underpinnings of this effect would constitute a massive undertaking that may require years of follow-up work.

 

Relatedly, do other growth factors have similar effects on ΔmtDNA proliferation?

BG and MP: It certainly seems plausible, but we do not know for sure. At the very least, growth factors that stimulate cell proliferation will inevitably generate more niche space in which mitochondrial genomes can compete for allele prevalence. However, this does not appear to be sufficient to explain why one genotype would have a selection advantage over another. One clue we seem to be seeing with our work on the insulin signaling pathway is the role of FoxO/DAF-16. This protein has previously been reported as a regulator of genes involved in mitochondrial respiration and the scavenging of reactive oxygen species. One interesting hypothesis that emerges from these studies, in conjunction with our study, is that the ability to preserve energy production and stave off cellular damage may be inadvertently providing an avenue for cheaters to proliferate. If that is indeed the case, then growth factors that also regulate energy production or stress tolerance are likely to similarly promote the proliferation of cheater genomes.

 

Your work specifically addresses mtDNA in the germline, but is it germline-specific? Do somatic mitochondria follow the same selection patterns of ΔmtDNA proliferation?

BG and MP: Somatic tissue types differ from one another in their energy demand as well as their gene expression patterns. Accordingly, we do not expect them to be all alike when it comes to mutant mitochondrial genome dynamics. There is some evidence for this, as previous studies have found evidence of tissue-specific segregation between different mtDNA genotypes within heteroplasmic animals. This phenomenon has now been observed in mammals and invertebrates. Dissecting the molecular basis for tissue-specific mutant mtDNA levels is now part of an ongoing area of focus in our lab. In this study we chose to focus on germline selection for two principle reasons. Firstly, the vast majority of mtDNA in the adult nematode is located within the female germline, so that when we detect changes in mutant mtDNA levels at the whole-organism level, most of what we are seeing reflects the biology of the germline. Secondly, the female germline is where mtDNA variants compete for transmission to the next generation, so this is really where the focus needs to be if we want to take an evolutionary approach that takes the different levels of selection into account.

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