Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging

Abstract

Summary While environmental stress likely plays a significant role in promoting aging, the relationship remains poorly understood. In order to characterize this interaction in a more comprehensive manner, we examined the stress response profiles for 46 long-lived yeast mutant strains across four different stress conditions (oxidative, ER, DNA damage, and thermal), grouping genes based on their associated stress response profiles. Unexpectedly, cells lacking the mitochondrial AAA protease gene AFG3 clustered strongly with long-lived strains lacking cytosolic ribosomal proteins of the large subunit. Similar to these ribosomal protein mutants, afg3Δ cells show reduced cytoplasmic mRNA translation, enhanced resistance to tunicamycin that is independent of the ER unfolded protein response, and Sir2-independent but Gcn4-dependent life span extension. These data demonstrate an unexpected link between a mitochondrial protease, cytoplasmic mRNA translation, and aging.

Proline Biosynthesis Is Required for Endoplasmic Reticulum Stress Tolerance in Saccharomyces cerevisiae

“…Yeast mutants deficient for ribosomal large subunits or with less cytosolic mRNA were found to be more resistant to Tm, which may be due to lower protein synthesis overall (58,59). In agreement with this notion, we found that limiting leucine, uracil, and histidine slightly improved tolerance to Tm.…”

Mitochondrial unfolded protein response gene Clpp is required to maintain ovarian follicular reserve during aging, for oocyte competence, and development of pre‐implantation embryos

“…In a paradoxical way, in yeast (Delaney et al., 2013), worms (Dillin et al., 2002), flies (Owusu‐Ansah, Song & Perrimon, 2013), and mice (Liu et al., 2005), suppression of mitochondrial ETC function increases lifespan (Dell'agnello et al., 2007; Durieux, Wolff & Dillin, 2011). While counterintuitive, these findings are supported by reports demonstrating that upregulation of mitochondrial stress response contributes to enhanced longevity in the long‐lived mitochondrial mutants (Durieux et al., 2011; Kirchman, Kim, Lai & Jazwinski, 1999).…”

“…Mitochondrial unfolded protein response and the role of CLPP seem to be conserved in mammals (Benedetti et al., 2006; Zhao et al., 2002), where activation of JNK/c‐JUN pathway leads to the expression of transcription factor C/EBP‐homologous protein (CHOP), which, together with C/EBP, mediates the transcription of mtUPR genes (reviewed in Hill & Van Remmen, 2014). It is important that, in addition to inducing transcription of over 400 genes, mtUPR in yeast, C. elegans , and mammals are associated with phosphorylation of eukaryotic initiation factor 2 alpha (eIF2a) by general control nonderepressible 2 (GCN2), resulting in global suppression of translation while mRNAs that contain upstream open reading frames (uORFs) are preferentially translated (Delaney et al., 2013; Rath et al., 2012). Transcriptional activation of mtUPR genes and translational suppression seem to be mediated by two parallel mechanisms, both requiring CLPP (Aldridge et al., 2007; Benedetti et al., 2006; Haynes et al., 2007; Zhao et al., 2002) and reviewed in (Jensen & Jasper, 2014; Schulz & Haynes, 2015).…”

UPRmt-mediated cytoprotection and organismal aging

“…Recent work has demonstrated that an increase in eukaryotic translation initiation factor 2 alpha (eIF2α) phosphorylation occurs in response to mitochondrial stress in both worms and mammals [6, 63–65] resulting in the attenuation of global protein synthesis while preferentially translating those mRNAs that contain upstream open reading frames (uORFs) [66]. Four eIF2α kinases exist, but in yeast, C. elegans , and mammals, the kinase general control non-derepressible 2 (GCN2) appears to contribute the most to the induced eIF2α phosphorylation that occurs during mitochondrial stress [6, 63, 64, 67] (Figure 2). However PKR, an eIF2α kinase that responds to double stranded RNA, has also been shown to be required for eIF2α phosphorylation during mitochondrial stress in the mouse intestine suggesting mitochondrial dysfunction activates multiple eIF2α kinases [65].…”