Absence of Mitochondrial Translation Control Proteins Extends Life Span by Activating Sirtuin-Dependent Silencing

Abstract

Altered mitochondrial functionality can extend organism life span, but the underlying mechanisms are obscure. Here we report that inactivating SOV1, a member of the yeast mitochondrial translation control (MTC) module, causes a robust Sir2-dependent extension of replicative life span in the absence of respiration and without affecting oxidative damage. We found that SOV1 interacts genetically with the cAMP-PKA pathway and the chromatin remodeling apparatus. Consistently, Sov1p-deficient cells displayed reduced cAMP-PKA signaling and an elevated, Sir2p-dependent, genomic silencing. Both increased silencing and life span extension in sov1Δ cells require the PKA/Msn2/4p target Pnc1p, which scavenges nicotinamide, a Sir2p inhibitor. Inactivating other members of the MTC module also resulted in Sir2p-dependent life span extension. The data demonstrate that the nuclear silencing apparatus senses and responds to the absence of MTC proteins and that this response converges with a pathway for life span extension elicited by reducing TOR signaling.

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging

“…We also saw increased RLS upon deletion of the genes encoding 2 mitochondrial tRNA synthetases, MSK1 and MSW1 , and three mitochondrial translation control (MTC) genes, SOV1, SUV3 , and CBS1 , which themselves affect levels of mitochondrial ribosomal proteins. Deletion of these three MTC genes has been shown previously to extend yeast RLS (Caballero et al, 2011). The bias toward the large subunit seen in the RLS-extending cytosolic ribosome deletions is repeated in the mitochondrial ribosome.…”

Mitochondrial stress signaling in longevity: A new role for mitochondrial function in aging

“…Lifespan extension and resistance to oxidative stress through this pathway requires an active target of rapamycin complex 1 (TORC1) and transcription factor Sfp1, a regulator of cytoplasmic translation. Another mitochondrial–nuclear transduction pathway independent of retrograde signaling mediates nuclear genomic silencing in a Sir2 histone deacetylase dependent manner [27]. Disruption in the mitochondrial translation complex activates this pathway and promotes longevity.…”

Peroxiredoxins, gerontogenes linking aging to genome instability and cancer

“…Sir2-dependent control of yeast aging appears interconnected with nutrient signaling, as reduced activity of TOR extends replicative life span, at least in part, by boosting Sir2 activity (Anderson et al 2003;Medvedik et al 2007; see also Steffen et al 2008). Likewise, life span extension achieved by reducing the activity of the yeast mitochondrial translation control module (MTC) acts through Sir2 activation (Caballero et al 2011).…”