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Nuclear genomic control of naturally occurring variation in mitochondrial function in Drosophila melanogaster.

Jumbo-Lucioni P, Bu S, Harbison ST, Slaughter JC, Mackay TF, Moellering DR, De Luca M - BMC Genomics (2012)

Bottom Line: We found significant within-population genetic variability for all mitochondrial traits.Our results provide novel insights into the genetic factors regulating natural variation in mitochondrial function in D. melanogaster.The integrative genomic approach used in our study allowed us to identify sls as a novel hub gene responsible for the regulation of mitochondrial respiration in muscle sarcomere and to provide evidence that sls might act via the electron transfer flavoprotein/ubiquinone oxidoreductase complex.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

ABSTRACT

Background: Mitochondria are organelles found in nearly all eukaryotic cells that play a crucial role in cellular survival and function. Mitochondrial function is under the control of nuclear and mitochondrial genomes. While the latter has been the focus of most genetic research, we remain largely ignorant about the nuclear-encoded genomic control of inter-individual variability in mitochondrial function. Here, we used Drosophila melanogaster as our model organism to address this question.

Results: We quantified mitochondrial state 3 and state 4 respiration rates and P:O ratio in mitochondria isolated from the thoraces of 40 sequenced inbred lines of the Drosophila Genetic Reference Panel. We found significant within-population genetic variability for all mitochondrial traits. Hence, we performed genome-wide association mapping and identified 141 single nucleotide polymorphisms (SNPs) associated with differences in mitochondrial respiration and efficiency (P ≤1 × 10-5). Gene-centered regression models showed that 2-3 SNPs can explain 31, 13, and 18% of the phenotypic variation in state 3, state 4, and P:O ratio, respectively. Most of the genes tagged by the SNPs are involved in organ development, second messenger-mediated signaling pathways, and cytoskeleton remodeling. One of these genes, sallimus (sls), encodes a component of the muscle sarcomere. We confirmed the direct effect of sls on mitochondrial respiration using two viable mutants and their coisogenic wild-type strain. Furthermore, correlation network analysis revealed that sls functions as a transcriptional hub in a co-regulated module associated with mitochondrial respiration and is connected to CG7834, which is predicted to encode a protein with mitochondrial electron transfer flavoprotein activity. This latter finding was also verified in the sls mutants.

Conclusions: Our results provide novel insights into the genetic factors regulating natural variation in mitochondrial function in D. melanogaster. The integrative genomic approach used in our study allowed us to identify sls as a novel hub gene responsible for the regulation of mitochondrial respiration in muscle sarcomere and to provide evidence that sls might act via the electron transfer flavoprotein/ubiquinone oxidoreductase complex.

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Variation in mitochondrial respiration traits among 40 of the DGRP wild-derived inbred lines. (Panels A-C) Distributions of line means for mitochondrial state 3 (Panel A) and state 4 (Panel B) respiration rates and P:O ratio (Panel C). Data represent means ± standard errors for n = 7 independent replicates. The red and blue bars depict females and males, respectively. (Panel D) Phenotypic correlation (r) between state 3 and state 4 respiration rates in the sex-pooled analysis. (Panel E) Phenotypic correlation between P:O ratio and state 3 in the sex-pooled analysis. (Panel F) Phenotypic correlation between P:O ratio and state 4 in females.
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Figure 1: Variation in mitochondrial respiration traits among 40 of the DGRP wild-derived inbred lines. (Panels A-C) Distributions of line means for mitochondrial state 3 (Panel A) and state 4 (Panel B) respiration rates and P:O ratio (Panel C). Data represent means ± standard errors for n = 7 independent replicates. The red and blue bars depict females and males, respectively. (Panel D) Phenotypic correlation (r) between state 3 and state 4 respiration rates in the sex-pooled analysis. (Panel E) Phenotypic correlation between P:O ratio and state 3 in the sex-pooled analysis. (Panel F) Phenotypic correlation between P:O ratio and state 4 in females.

Mentions: We found significant differences in the function of thoracic mitochondria isolated from the 40 DGRP lines (Figure 1 and Table 1). Our results indicate that 20%, 15%, and 17% of the variability in mitochondrial state 3, state 4, and P:O ratio, respectively, is attributed to genetic factors. We also observed significant differences between males and females, with females on average having higher mitochondrial respiration rates (Figure 1A and B) and coupling efficiency (Figure 1C) than males. Despite marked sexual dimorphism, the direction of the sex differences for state 3 and state 4 respiration rates was not affected by the genotype in our sample, as indicated by the absence of significant line-by-sex interactions (Table 1). A marginal effect, however, was found for P:O ratio (Table 1), suggesting that some of the loci regulating mitochondrial efficiency might have a sex-specific effect.


Nuclear genomic control of naturally occurring variation in mitochondrial function in Drosophila melanogaster.

Jumbo-Lucioni P, Bu S, Harbison ST, Slaughter JC, Mackay TF, Moellering DR, De Luca M - BMC Genomics (2012)

Variation in mitochondrial respiration traits among 40 of the DGRP wild-derived inbred lines. (Panels A-C) Distributions of line means for mitochondrial state 3 (Panel A) and state 4 (Panel B) respiration rates and P:O ratio (Panel C). Data represent means ± standard errors for n = 7 independent replicates. The red and blue bars depict females and males, respectively. (Panel D) Phenotypic correlation (r) between state 3 and state 4 respiration rates in the sex-pooled analysis. (Panel E) Phenotypic correlation between P:O ratio and state 3 in the sex-pooled analysis. (Panel F) Phenotypic correlation between P:O ratio and state 4 in females.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3526424&req=5

Figure 1: Variation in mitochondrial respiration traits among 40 of the DGRP wild-derived inbred lines. (Panels A-C) Distributions of line means for mitochondrial state 3 (Panel A) and state 4 (Panel B) respiration rates and P:O ratio (Panel C). Data represent means ± standard errors for n = 7 independent replicates. The red and blue bars depict females and males, respectively. (Panel D) Phenotypic correlation (r) between state 3 and state 4 respiration rates in the sex-pooled analysis. (Panel E) Phenotypic correlation between P:O ratio and state 3 in the sex-pooled analysis. (Panel F) Phenotypic correlation between P:O ratio and state 4 in females.
Mentions: We found significant differences in the function of thoracic mitochondria isolated from the 40 DGRP lines (Figure 1 and Table 1). Our results indicate that 20%, 15%, and 17% of the variability in mitochondrial state 3, state 4, and P:O ratio, respectively, is attributed to genetic factors. We also observed significant differences between males and females, with females on average having higher mitochondrial respiration rates (Figure 1A and B) and coupling efficiency (Figure 1C) than males. Despite marked sexual dimorphism, the direction of the sex differences for state 3 and state 4 respiration rates was not affected by the genotype in our sample, as indicated by the absence of significant line-by-sex interactions (Table 1). A marginal effect, however, was found for P:O ratio (Table 1), suggesting that some of the loci regulating mitochondrial efficiency might have a sex-specific effect.

Bottom Line: We found significant within-population genetic variability for all mitochondrial traits.Our results provide novel insights into the genetic factors regulating natural variation in mitochondrial function in D. melanogaster.The integrative genomic approach used in our study allowed us to identify sls as a novel hub gene responsible for the regulation of mitochondrial respiration in muscle sarcomere and to provide evidence that sls might act via the electron transfer flavoprotein/ubiquinone oxidoreductase complex.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

ABSTRACT

Background: Mitochondria are organelles found in nearly all eukaryotic cells that play a crucial role in cellular survival and function. Mitochondrial function is under the control of nuclear and mitochondrial genomes. While the latter has been the focus of most genetic research, we remain largely ignorant about the nuclear-encoded genomic control of inter-individual variability in mitochondrial function. Here, we used Drosophila melanogaster as our model organism to address this question.

Results: We quantified mitochondrial state 3 and state 4 respiration rates and P:O ratio in mitochondria isolated from the thoraces of 40 sequenced inbred lines of the Drosophila Genetic Reference Panel. We found significant within-population genetic variability for all mitochondrial traits. Hence, we performed genome-wide association mapping and identified 141 single nucleotide polymorphisms (SNPs) associated with differences in mitochondrial respiration and efficiency (P ≤1 × 10-5). Gene-centered regression models showed that 2-3 SNPs can explain 31, 13, and 18% of the phenotypic variation in state 3, state 4, and P:O ratio, respectively. Most of the genes tagged by the SNPs are involved in organ development, second messenger-mediated signaling pathways, and cytoskeleton remodeling. One of these genes, sallimus (sls), encodes a component of the muscle sarcomere. We confirmed the direct effect of sls on mitochondrial respiration using two viable mutants and their coisogenic wild-type strain. Furthermore, correlation network analysis revealed that sls functions as a transcriptional hub in a co-regulated module associated with mitochondrial respiration and is connected to CG7834, which is predicted to encode a protein with mitochondrial electron transfer flavoprotein activity. This latter finding was also verified in the sls mutants.

Conclusions: Our results provide novel insights into the genetic factors regulating natural variation in mitochondrial function in D. melanogaster. The integrative genomic approach used in our study allowed us to identify sls as a novel hub gene responsible for the regulation of mitochondrial respiration in muscle sarcomere and to provide evidence that sls might act via the electron transfer flavoprotein/ubiquinone oxidoreductase complex.

Show MeSH
Related in: MedlinePlus