Nutrient status shapes selfish mitochondrial genome dynamics across different levels of selection

Abstract

Cooperation and cheating are widespread evolutionary strategies. While cheating confers an advantage to individual entities within a group, competition between groups favors cooperation. Selfish or cheater mitochondrial DNA (mtDNA) proliferates within hosts while being selected against at the level of host fitness. How does environment shape cheater dynamics across different selection levels? Focusing on food availability, we address this question using heteroplasmic Caenorhabditis elegans. We find that the proliferation of selfish mtDNA within hosts depends on nutrient status stimulating mtDNA biogenesis in the developing germline. Interestingly, mtDNA biogenesis is not sufficient for this proliferation, which also requires the stress-response transcription factor FoxO/DAF-16. At the level of host fitness, FoxO/DAF-16 also prevents food scarcity from accelerating the selection against selfish mtDNA. This suggests that the ability to cope with nutrient stress can promote host tolerance of cheaters. Our study delineates environmental effects on selfish mtDNA dynamics at different levels of selection.

Avoiding Extinction: Recent Advances in Understanding Mechanisms of Mitochondrial DNA Purifying Selection in the Germline

“…As expected of such a severe deletion, heteroplasmic uaDf5 strains have reduced fitness in terms of egg laying, sperm motility, and longevity, which correlates with the percentage of mutant uaDf5 mtDNA present (89,91). Consistent with its pathogenicity, this deleterious genome is subject to purifying selection in the female germline, as progeny show significantly reduced levels of mutant uaDf5 mtDNA compared with their heteroplasmic parents (2,51). mtDNA selection has also been observed in certain strains of Caenorhabditis briggsae harboring a mutant genome carrying a deletion in nduo-5, a homolog of human MT-ND5 (131).…”

“…The degree to which a specific mutation remains present in a heteroplasmic cell is influenced by the characteristics of the mtDNA mutation in question. In certain cell types, some mutated mitochondrial genomes may replicate better than others or evade copy number control (38,51,93,131), while others might impair mtDNA replication or promote mtDNA turnover, as in, for example, female germ cells, which we discuss in great detail below (64,148). Furthermore, even some apparently wild-type mitochondrial haplotypes show biased segregation when heteroplasmic, varying in degree depending both on the cell type and on the nuclear background (reviewed Purifying selection (acts on some deleterious mutants)…”

“…Studies have shown strong evidence for negative (purifying) selection in mtDNA using pedigree analysis (61,107) and by measuring the ratio of nonsynonymous (more likely to be deleterious) to synonymous (less likely to be deleterious) mutations from a variety of sampled vertebrate and invertebrate species (101,114). This purifying selection is thought to be the main mechanism for maintaining mtDNA function over generations in light of a high mutation rate (2,30,31,43,51,57,90,94,130,131).…”

Tissue-specific heteroplasmy dynamics is accompanied by a sharp drop in mtDNA copy number during development

“…Alternatively, the effect may be caused by a reduction in AMPK-mediated biogenesis. However, this possibility seems unlikely given that mitochondrial biogenesis favors mutant mtDNA proliferation (Lin et al, 2016, Gitschlag et al, 2020. Moreover, our data show that somatic mtDNA copy number declines continuously throughout C. elegans lifespan, suggesting more degradation than biogenesis.…”

“…Heteroplasmic mutant strains were crossed into transgenic lines expressing GFP pan-neuronally or in body wall muscles (Altun-Gultekin et al, 2001, Haynes et al, 2007. The best studied C. elegans mtDNA deletion (3.1 Kb uaDf5) (Tsang and Lemire, 2002b) affects multiple protein-coding genes and tRNAs (Figure 2B) to impact cellular respiration, increase mitochondrial stress and reduce viability, with lower brood size and slower growth rate (Liau et al, 2007, Lin et al, 2016, Gitschlag et al, 2020. We first examined uaDf5 levels in neurons and muscles of adult animals (Day 1) from pools of 200 cells, which provided sufficient mtDNA templates for ddPCR while also allowing us to collect multiple batches of cells.…”