Neuronal expression of a single‐subunit yeast NADH–ubiquinone oxidoreductase (Ndi1) extends Drosophila lifespan

Abstract

SummaryThe 'rate of living' theory predicts that longevity should be inversely correlated with the rate of mitochondrial respiration. However, recent studies in a number of model organisms, including mice, have reported that interventions that retard the aging process are, in fact, associated with an increase in mitochondrial activity. To better understand the relationship between energy metabolism and longevity, we supplemented the endogenous respiratory chain machinery of the fruit fly Drosophila melanogaster with the alternative single-subunit NADHubiquinone oxidoreductase (Ndi1) of the baker's yeast Saccharomyces cerevisiae. Here, we report that expression of Ndi1 in fly mitochondria leads to an increase in NADH-ubiquinone oxidoreductase activity, oxygen consumption, and ATP levels. In addition, exogenous Ndi1 expression results in increased CO 2 production in living flies. Using an inducible gene-expression system, we expressed Ndi1 in different cells and tissues and examined the impact on longevity. In doing so, we discovered that targeted expression of Ndi1 in fly neurons significantly increases lifespan without compromising fertility or physical activity. These findings are consistent with the idea that enhanced respiratory chain activity in neuronal tissue can prolong fly lifespan.

Interplay of dFOXO and Two ETS-Family Transcription Factors Determines Lifespan in Drosophila melanogaster

“…Indeed, part of the effect of dFOXO on lifespan could be mediated by its repression of the components of complex I, because reducing the electron flow through this complex, by bypassing it, can extend fly lifespan [41], [42].…”

Complex-I-ty in aging

“…One of these, NADH dehydrogenase internal 1 ( ndi1 ) is functional in higher metazoans, including mammals, acting as a non-proton translocating NADH dehydrogenase/ubiquinone oxidoreductase in the mitochondrial matrix (Yagi et al 2006). Transgenic expression of ndi1 in D. melanogaster rescues loss of endogenous complex I (Cho et al 2012) and expression in flies without complex I defects supplements and boosts endogenous NADH dehydrogenase/ubiquinone oxidoreductase activity in a rotenone-insensitive manner (Sanz et al 2010; Bahadorani et al 2010; Hur et al 2013). Critically, unlike dPGC-1 , this increase in complex I-like activity was achieved without significant changes to other ETC complexes (Sanz et al 2010; Bahadorani et al 2010).…”

“…Transgenic expression of ndi1 in D. melanogaster rescues loss of endogenous complex I (Cho et al 2012) and expression in flies without complex I defects supplements and boosts endogenous NADH dehydrogenase/ubiquinone oxidoreductase activity in a rotenone-insensitive manner (Sanz et al 2010; Bahadorani et al 2010; Hur et al 2013). Critically, unlike dPGC-1 , this increase in complex I-like activity was achieved without significant changes to other ETC complexes (Sanz et al 2010; Bahadorani et al 2010). Like dPGC-1 , expression of ndi1 in flies resulted in increased markers of complex I-like activity, extended longevity, and reduced ROS levels (Sanz et al 2010; Bahadorani et al 2010; Hur et al 2013).…”

Ciona intestinalis NADH dehydrogenase NDX confers stress-resistance and extended lifespan on Drosophila

“…Additionally, yeast Ndi1 has been shown to have therapeutic benefit in several Parkinson's disease models [14][15][16][17][18][19] and evidence supporting a possible use in anti-cancer treatment has also been put forward [20]. Many other physiological effects were also reported in model organisms expressing yeast Ndi1, including extended lifespan [9,21] and resistance to particular stresses [9]. Intriguingly, the alternative NADH dehydrogenases show some sequence similarity with AIF (apoptosis-inducing factor) and the S. cerevisiae Ndi1 protein has been shown to be capable of inducing apoptosis [22,23].…”

“…Whilst the therapeutic potential of alternative NADH dehydrogenase has been demonstrated on diverse models, using S. cerevisiae Ndi1 [8][9][10][11][12][13][14][15][16][17][18][19][20][21], the yeast enzyme may not be optimal for such use, for several reasons. First, and most importantly, it exists in vivo without the presence of cI.…”