Extension of chronological life span by reduced TOR signaling requires down-regulation of Sch9p and involves increased mitochondrial OXPHOS complex density

Abstract

The nutrient-sensing target of rapamycin (TOR) pathway appears to have a conserved role in regulating life span. This signaling network is complex, with many downstream physiological outputs, and thus the mechanisms underlying its age-related effects have not been elucidated fully. We demonstrated previously that reduced TOR signaling (intor1Δ strains) extends yeast chronological life span (CLS) by increasing mitochondrial oxygen consumption, in part, by up-regulating translation of mtDNA-encoded oxidative phosphorylation (OXPHOS) subunits. Here, we have examined in greater detail how TOR signaling influences mitochondrial function and CLS and the role of the Sch9p kinase in the TOR-mitochondria pathway. As is the case for oxygen consumption, mitochondrial translation is elevated in tor1Δ strains only during active growth and early stationary phase growth points. This is accompanied by a corresponding increase in the abundance of both mtDNA-encoded and nucleus-encoded OXPHOS subunits per mitochondrial mass. However, this increased OXPHOS complex density is not associated with more mitochondria/cell or cellular ATP and leads to an overall decrease in membrane potential, suggesting that TOR signaling may influence respiration uncoupling. Finally, we document that the Sch9p kinase is a key downstream effector of OXPHOS, ROS and CLS in the TOR-mitochondria pathway. Altogether, our results demonstrate that TOR signaling has a global role in regulating mitochondrial proteome dynamics and function that is important for its role in aging and provide compelling evidence for involvement of a "mitochondrial pre-conditioning" effect in CLS determination.

Unopposed mitochondrial fission leads to severe lifespan shortening

“…4B), indicating that survival of Δmgm1 in stationary phase cells is severely compromised. Since it is known that survival of yeast in this phase depends on the ability to degrade cellular components by autophagy and on resistance to oxidative stress, among other factors, [33][34][35] it is tempting to speculate that the short-lived phenotype of the Δmgm1 mutant is due to ineffective mobilization of cellular resources or the result of the accumulation of oxidative damage to vital cellular components. Indeed, it was recently shown that energetically compromised mitochondria inhibit both induction of autophagy and the autophagic flux in baker's yeast.…”

TOR and ageing: a complex pathway for a complex process

“…Reduced TOR function leads to enhanced respiratory capacity in the absence of enhanced mitochondrial biogenesis, and this is required for chronological lifespan extension [50,95]. Instead of enhanced biogenesis, the result of reduced TOR signalling is more OXPHOS complexes per mitochondrion [96]. Moreover, ATP production is not elevated.…”

“…These findings lead the authors to speculate that these changes, which happen during cell proliferation and early cell cycle stages, precondition cells to a state promoting prolonged survival during the growth arrested period. Deletion of yeast S6 kinase (sch9), which also promotes enhanced chronological lifespan [97], is also linked to these changes in respiration [96,98]. Unlike chronological ageing, extension of yeast replicative lifespan by sch9D is not impaired by blocking accompanying enhancement of respiration [98].…”

Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations

“…Inhibition of the mTORC1 signaling pathway extends lifespan in various model animals, ranging from yeast (Kaeberlein et al, 2005a;Bonawitz et al, 2007;Pan and Shadel, 2009), C. elegans (Vellai et al, 2003), fly (Kapahi et al, 2004), to rodents (Harrison et al, 2009;Selman et al, 2009), thus establishing a close relationship between metabolism and aging. Studies from invertebrate models first demonstrated that inhibition of the mTOR signaling pathway is sufficient to reduce protein synthesis and increase lifespan (Vellai et al, 2003;Kapahi et al, 2004;Kaeberlein and Kennedy, 2008;Stanfel et al, 2009).…”