Nuclear-mitochondrial epistasis and drosophila aging: introgression of Drosophila simulans mtDNA modifies longevity in D. melanogaster nuclear backgrounds

Abstract

Under the mitochondrial theory of aging, physiological decline with age results from the accumulated cellular damage produced by reactive oxygen species generated during electron transport in the mitochondrion. A large body of literature has documented age-specific declines in mitochondrial function that are consistent with this theory, but relatively few studies have been able to distinguish cause from consequence in the association between mitochondrial function and aging. Since mitochondrial function is jointly encoded by mitochondrial (mtDNA) and nuclear genes, the mitochondrial genetics of aging should be controlled by variation in (1) mtDNA, (2) nuclear genes, or (3) nuclear-mtDNA interactions. The goal of this study was to assess the relative contributions of these factors in causing variation in Drosophila longevity. We compared strains of flies carrying mtDNAs with varying levels of divergence: two strains from Zimbabwe (<20 bp substitutions between mtDNAs), strains from Crete and the United States (approximately 20-40 bp substitutions between mtDNAs), and introgression strains of Drosophila melanogaster carrying mtDNA from Drosophila simulans in a D. melanogaster Oregon-R chromosomal background (>500 silent and 80 amino acid substitutions between these mtDNAs). Longevity was studied in reciprocal cross genotypes between pairs of these strains to test for cytoplasmic (mtDNA) factors affecting aging. The intrapopulation crosses between Zimbabwe strains show no difference in longevity between mtDNAs; the interpopulation crosses between Crete and the United States show subtle but significant differences in longevity; and the interspecific introgression lines showed very significant differences between mtDNAs. However, the genotypes carrying the D. simulans mtDNA were not consistently short-lived, as might be predicted from the disruption of nuclear-mitochondrial coadaptation. Rather, the interspecific mtDNA strains showed a wide range of variation that flanked the longevities seen between intraspecific mtDNAs, resulting in very significant nuclear x mtDNA epistatic interaction effects. These results suggest that even "defective" mtDNA haplotypes could extend longevity in different nuclear allelic backgrounds, which could account for the variable effects attributable to mtDNA haplogroups in human aging.

Figure 1.

Survival of parental and reciprocal cross genotypes of two Zimbabwe strains of D. melanogaster. The parental strains (Zimbabwe 2 and Zimbabwe 53) are significantly different from each other, and from either reciprocal cross (P < 0.001, log-rank test). The two reciprocal genotypes are not significantly different for females, and are significantly different for males (P < 0.01, log-rank test).

Figure 2.

Survival and mortality plots for females. Data for reciprocal crosses between two strains (female × male) are shown. (A and B) Reciprocal crosses between the two D. melanogaster wild strains FTF 100 and Crete 10. (C–J) Crosses between one D. melanogaster strain and a sim-mel introgression strain (sm21 or sm38). Blue squares, FTF 100 cytoplasm; pink dots, Crete 10 cytoplasm; open circles, sm38 cytoplasm; open squares, sm21 cytoplasm. Red signifies a D. simulans mtDNA. Each pair of genotypes is significantly different using log-rank tests of survivorship after correcting for multiple tests (P < 0.001), but data in A and B and I and J show no significant difference in mortality parameters (see results and Table 1).

Figure 3.

Survivorship and mortality plots for males. Same reciprocal cross format as Figure 2, but note that reciprocal cross males can differ in X- and Y-linked polymorphisms. Only genotype pairs in C and I are significantly different using log-rank tests of survivorship after correcting for multiple tests (P < 0.001).

Figure 4.

Survival plots for all reciprocal genotypes. The two reciprocal crosses carrying D. melanogaster mtDNAs (labeled 1 and 2) are intermediate to the reciprocal genotypes carrying either D. melanogaster or D. simulans mtDNA (reciprocal cross genotypes are numbered sequentially and are shown in the same color).

Figure 5.

Nuclear–mitochondrial epistasis for longevity. Median longevity, in days, is plotted for pairs of reciprocal crosses. Reciprocal genotypes have the same symbol connected by a line, analogous to reaction norms for hybrid nuclear genotypes in alternative mtDNA environments. The X-axis shows the mtDNA present in each genotype (Dmel signifies either Crete or FTF; Dsim signifies either sm21 or sm38). A plot with mean values is very similar. Error bars are omitted, but all interaction effects are highly significant (see Table 2).