A Mitochondrial ATP Synthase Subunit Interacts with TOR Signaling to Modulate Protein Homeostasis and Lifespan in Drosophila

Abstract

SUMMARY Diet composition is a critical determinant of lifespan and nutrient imbalance is detrimental health. However, how nutrients interact with genetic factors to modulate lifespan remains elusive. We investigated how diet composition influences mitochondrial ATP synthase subunit d (ATPsyn-d) in modulating lifespan in Drosophila. ATPsyn-d knockdown extended lifespan in females fed low carbohydrate-to-protein (C:P) diets, but not the high C:P ratio diet. This extension was associated with increased resistance to oxidative stress, transcriptional changes in metabolism, proteostasis and immune genes, reduced protein damage and aggregation, and reduced phosphorylation of S6K and ERK in TOR and MAPK signaling, respectively. ATPsyn-d knockdown did not extend lifespan in females with reduced TOR signaling induced genetically by Tsc2 overexpression or pharmacologically by rapamycin. Our data reveal a link among diet, mitochondria, MAPK and TOR signaling in aging and stresses the importance of considering genetic background and diet composition in implementing interventions for promoting healthy aging.

2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling

“…Inhibition of ATP synthase leads to decreased TOR signaling in mammalian cells, worms, and flies (Chin et al, 2014; Sun et al, 2014). We found that ATP5B knockdown (Figure 4G), treatment with octyl esters of 2-HG (Figure 4H), and IDH1(R132H) mutation (Figure 4I) all decrease the phosphorylation of mTOR complex 1 substrates.…”

Mitochondrial maintenance failure in aging and role of sexual dimorphism

“…In mice with an ETC complex III gene mutation, males have reduced life span, whereas females show a subset with increased life span [131]. Drosophila studies have identified many QTLs and genes with sex-specific and sexually-antagonistic effects on aging and mitochondrial function [73, 110, 132–136]. For example, Drosophila p53 exhibits developmental stage-specific and sex-specific effects on adult life span indicative of SAP [137], and these effects are modulated in a sex-specific way by foxo [82, 138].…”

Hair regeneration by small molecules that activate autophagy

“…Our finding that the well-established complex V inhibitor oligomycin in fact promotes hair regeneration suggested that possibly, as in lifespan regulation, mild mitochondrial inhibition may prove to be beneficial. Since mitochondrial complex V acts upstream of TOR from C. elegans to Drosophila and humans (Chin et al, 2014;Sun et al, 2014;Fu et al, 2015), and autophagy is induced both by mitochondrial complex V inhibition ( Figure 1D) and by TOR inhibition ( Figure 2C) (see also (Chin et al, 2014)), we further tested if autophagy induction itself is sufficient for hair regeneration. To this end, we took advantage of a TOR-independent autophagy inducing small molecule, SMER28 (Sarkar et al, 2007).…”