Sirt4 Modulates Oxidative Metabolism and Sensitivity to Rapamycin Through Species-Dependent Phenotypes in Drosophila mtDNA Haplotypes

• Published in: G3 : genes - genomes - genetics Vol. 10; no. 5; pp. 1599 - 1612
• Main Authors: Sejour, Richard, Sanguino, Roger A, Mikolajczak, Monika, Ahmadi, Walishah, Villa-Cuesta, Eugenia
• Format: Journal Article
• Language: English
• Published: England Genetics Society of America 01-05-2020; Oxford University Press
• Subjects: Animals; coevolution mtdna/ndna; DNA, Mitochondrial - genetics; Drosophila - drug effects; Drosophila - genetics; Drosophila melanogaster - drug effects; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Haplotypes; Investigations; Mitochondria - genetics; Oxidative Stress; Phenotype; Sirolimus - pharmacology; sirt4; Sirtuins - genetics; tor pathway; TOR pathway; coevolution mtDNA/nDNA; Sirt4
• ISSN: 2160-1836; 2160-1836
• DOI: 10.1534/g3.120.401174

The endosymbiotic theory proposes that eukaryotes evolved from the symbiotic relationship between anaerobic (host) and aerobic prokaryotes. Through iterative genetic transfers, the mitochondrial and nuclear genomes coevolved, establishing the mitochondria as the hub of oxidative metabolism. To study this coevolution, we disrupt mitochondrial-nuclear epistatic interactions by using strains that have mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) from evolutionarily divergent species. We undertake a multifaceted approach generating introgressed
strains containing
mtDNA and
nDNA with
(
-knockouts. Sirt4 is a nuclear-encoded enzyme that functions, exclusively within the mitochondria, as a master regulator of oxidative metabolism. We exposed flies to the drug rapamycin in order to eliminate TOR signaling, thereby compromising the cytoplasmic crosstalk between the mitochondria and nucleus. Our results indicate that
and
mtDNA haplotypes display opposite Sirt4-mediated phenotypes in the regulation of whole-fly oxygen consumption. Moreover, our data reflect that the deletion of
rescued the metabolic response to rapamycin among the introgressed strains. We propose that Sirt4 is a suitable candidate for studying the properties of mitochondrial-nuclear epistasis in modulating mitochondrial metabolism.