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 (intor1Delta 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 tor1Delta 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.
Highlights
How and why we age has long been a fascination of humans
We have examined in greater mechanistic detail how the yeast target of rapamycin (TOR) pathway influences mitochondrial gene expression, oxidative phosphorylation (OXPHOS) activity, and proteome composition, and the role of the Sch9p kinase as a downstream mediator of its effects on mitochondria
One day later in stationary phase the wild-type and tor1Δ strains showed similar rates of mitochondrial translation, due to an increase in the rate in the wild-type strains (Figure 1). These results mirrored closely our previously published results on oxygen consumption as a function of growth state and demonstrate that the major differences in mitochondrial function in these strains are manifest during growth and early stationary phase, which is when TOR signaling is at its highest in wild-type strains
Summary
How and why we age has long been a fascination of humans. In addition to being of intrinsic philosophical, evolutionary and biological interest, determining the molecular and cellular mechanisms underlying the aging process is relevant to understanding age-related pathology that limits human life and health span. Model organism studies have been instrumental in understanding aging, with many conserved pathways and factors having been identified in files, worms and yeast (and other organisms) that have physiological and pathological relevance in humans [1]. One general area that has been implicated strongly in aging and life span determination is nutrient availability/sensing. Dietary (i.e. caloric) restriction extends life span and ameliorates many of the age-associated declines in cellular function in virtually all organisms examined to date [2].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
