Stimulating the sir2–spargel axis rescues exercise capacity and mitochondrial respiration in a Drosophila model of Barth syndrome

Abstract

Cardiolipin (CL) is a phospholipid required for proper mitochondrial function. Tafazzin remodels CL to create highly unsaturated fatty acid chains. However, when TAFAZZIN is mutated, CL remodeling is impeded, leading to mitochondrial dysfunction and the disease Barth syndrome. Patients with Barth syndrome often have severe exercise intolerance, which negatively impacts their overall quality of life. Boosting NAD+ levels can improve symptoms of other mitochondrial diseases, but its effect in the context of Barth syndrome has not been examined. We demonstrate, for the first time, that nicotinamide riboside can rescue exercise tolerance and mitochondrial respiration in a Drosophila Tafazzin mutant and that the beneficial effects are dependent on sir2 and spargel. Overexpressing spargel increased the total abundance of CL in mutants. In addition, muscles and neurons were identified as key targets for future therapies because sir2 or spargel overexpression in either of these tissues is sufficient to restore the exercise capacity of Drosophila Tafazzin mutants.

A novel panel of Drosophila TAFAZZIN mutants in distinct genetic backgrounds as a resource for therapeutic testing

“…These 2 lines had relatively average reductions in performance and mitochondrial RCR following TAZ deletion, so it is not obvious why they responded so well to NR treatment aside from the undefined influences of their genetic background. In the original TAZ mutant, NR supplementation was able to rescue endurance, climbing speed and mitochondrial RCR without any significant impact on WT background controls [ 20 ]. Here, for the most part, NR had no effect on WT performance or was mildly beneficial ( S2 Fig ).…”

“…Here, we provide an initial characterization of our 10 novel DGRP- TAZ mutants, describing the variable phenotypic severity in endurance, mobility, and mitochondrial respiration, as well as the first application of this panel for testing potential therapeutics. Supplementation with the NAD + precursor nicotinamide riboside (NR) was sufficient to improve both exercise and mitochondrial deficits in the original TAZ mutant background [ 20 , 22 ]. As proof of principle for the utility of this newly developed panel as a resource for representing phenotypic diversity and variable response to treatment, we fed NR to each of the DGRP- TAZ lines to assess how variations in genetic background alter efficacy.…”

“…Specific to BTHS, Drosophila mutants with deletions of the 3' region of the gene, thus lacking full-length functional TAZ, have been developed [8,19]. One of these deletion mutants contains an RFP knock-in at the deletion site to facilitate crossing into other genetic backgrounds, and this was the one used in this study [20]. Each of these models has been used effectively to aid in our understanding of the progression and biology of the disease, with the goal of developing effective therapies [8,[19][20][21].These Drosophila models have been instrumental in the discovery of pharmacological targets able to rescue exercise capacity and mitochondrial deficits [20,22].…”

“…One of these deletion mutants contains an RFP knock-in at the deletion site to facilitate crossing into other genetic backgrounds, and this was the one used in this study [20]. Each of these models has been used effectively to aid in our understanding of the progression and biology of the disease, with the goal of developing effective therapies [8,[19][20][21].These Drosophila models have been instrumental in the discovery of pharmacological targets able to rescue exercise capacity and mitochondrial deficits [20,22]. The TAZ mutant line used in these studies has been extensively characterized and has several conserved phenotypes with human BTHS [21].…”

Does Selection for Longevity in Acheta domesticus Involve Sirtuin Activity Modulation and Differential Response to Activators (Resveratrol and Nanodiamonds)?

“…Research findings have proved that resveratrol (RV; 3, 5, 4 ′ -trihydroxystilbene) acts as a sirtuin activator with specificity toward substrates. Moreover, RV can potentially influence an individual's survival time [21][22][23]. In the appropriate concentration, it can extend the life span of Saccharomyces cerevisiae by up to 70% [24].…”