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Dietary restriction (DR) is the most consistent means of extending longevity in a wide range of organisms. A growing body of literature indicates that mitochondria play an important role in longevity extension by DR, but the impact of mitochondrial genotypes on the DR process have received little attention. Mitochondrial function requires proper integration of gene products from their own genomes (mtDNA) and the nuclear genome as well as the metabolic state of the cell, which is heavily influenced by diet. These three-way mitochondrial-nuclear-dietary interactions influence cellular and organismal functions that affect fitness, aging, and disease in nature. To examine these interactions in the context of longevity, we generated 18 “mito-nuclear” genotypes by placing mtDNA from strains of Drosophila melanogaster and D. simulans onto controlled nuclear backgrounds of D. melanogaster (Oregon-R, w1118, SIR2 overexpression and control) and quantified the lifespan of each mitonuclear genotype on five different sugar:yeast diets spanning a range of caloric and dietary restriction (CR and DR). Using mixed effect models to quantify main and interaction effects, we uncovered strong mitochondrial-diet, mitochondrial-nuclear, and nuclear-diet interaction effects, in addition to three-way interactions. Survival analyses demonstrate that interaction effects can be more important than individual genetic or dietary effects on longevity. Overexpression of SIR2 reduces lifespan variation among different mitochondrial genotypes and further dampens the response of lifespan to CR but not to DR, suggesting that response to these two diets involve different underlying mechanisms. Overall the results reveal that mitochondrial-nuclear genetic interactions play important roles in modulating Drosophila lifespan and these epistatic interactions are further modified by diet. More generally, these findings illustrate that gene-by-gene and gene-by-environment interactions are not simply modifiers of key factors affecting longevity, but these interactions themselves are the very factors that underlie important variation in this trait. [ABSTRACT FROM AUTHOR]

Kidney function depends on the nephron, which comprises a blood filter, a tubule that is subdivided into functionally distinct segments, and a collecting duct. How these regions arise during development is poorly understood. The zebrafish pronephros consists of two linear nephrons that develop from the intermediate mesoderm along the length of the trunk. Here we show that, contrary to current dogma, these nephrons possess multiple proximal and distal tubule domains that resemble the organization of the mammalian nephron. We examined whether pronephric segmentation is mediated by retinoic acid (RA) and the caudal (cdx) transcription factors, which are known regulators of segmental identity during development. Inhibition of RA signaling resulted in a loss of the proximal segments and an expansion of the distal segments, while exogenous RA treatment induced proximal segment fates at the expense of distal fates. Loss of cdx function caused abrogation of distal segments, a posterior shift in the position of the pronephros, and alterations in the expression boundaries of raldh2 and cyp26a1, which encode enzymes that synthesize and degrade RA, respectively. These results suggest that the cdx genes act to localize the activity of RA along the axis, thereby determining where the pronephros forms. Consistent with this, the pronephric-positioning defect and the loss of distal tubule fate were rescued in embryos doubly -deficient for cdx and RA. These findings reveal a novel link between the RA and cdx pathways and provide a model for how pronephric nephrons are segmented and positioned along the embryonic axis. [ABSTRACT FROM AUTHOR]

Dietary restriction (DR) is the most consistent means of extending longevity in a wide range of organisms. A growing body of literature indicates that mitochondria play an important role in longevity extension by DR, but the impact of mitochondrial genotypes on the DR process have received little attention. Mitochondrial function requires proper integration of gene products from their own genomes (mtDNA) and the nuclear genome as well as the metabolic state of the cell, which is heavily influenced by diet. These three-way mitochondrial-nuclear-dietary interactions influence cellular and organismal functions that affect fitness, aging, and disease in nature. To examine these interactions in the context of longevity, we generated 18 "mito-nuclear" genotypes by placing mtDNA from strains of Drosophila melanogaster and D. simulans onto controlled nuclear backgrounds of D. melanogaster (Oregon-R, w1118, SIR2 overexpression and control) and quantified the lifespan of each mitonuclear genotype on five different sugar:yeast diets spanning a range of caloric and dietary restriction (CR and DR). Using mixed effect models to quantify main and interaction effects, we uncovered strong mitochondrial-diet, mitochondrial-nuclear, and nuclear-diet interaction effects, in addition to three-way interactions. Survival analyses demonstrate that interaction effects can be more important than individual genetic or dietary effects on longevity. Overexpression of SIR2 reduces lifespan variation among different mitochondrial genotypes and further dampens the response of lifespan to CR but not to DR, suggesting that response to these two diets involve different underlying mechanisms. Overall the results reveal that mitochondrial-nuclear genetic interactions play important roles in modulating Drosophila lifespan and these epistatic interactions are further modified by diet. More generally, these findings illustrate that gene-by-gene and gene-by-environment interactions are not simply modifiers of key factors affecting longevity, but these interactions themselves are the very factors that underlie important variation in this trait.