UPRmt-mediated cytoprotection and organismal aging

Abstract

Time or age-dependent accumulation of mitochondrial damage and dysfunction is strongly associated with aging [1]. Thus, a major biomedical goal is to identify and therapeutically manipulate those inherent programs that protect against mitochondrial dysfunction to promote cell survival and organismal health. The mitochondrial unfolded protein response (UPRmt) is such a protective transcriptional response mediated by mitochondrial-to-nuclear signaling that includes mitochondrial proteostasis genes to stabilize mitochondrial function, metabolic adaptations, as well as an innate immunity program. Here, we review the UPRmt and its role during a variety of forms of mitochondrial dysfunction including those caused by mutations in respiratory chain genes as well as upon exposure to pathogens that produce mitochondrial toxins. We also review recent data in support of and against the emerging role of the UPRmt during aging and longevity.

Mitochondrial responsibility in ageing process: innocent, suspect or guilty

“…Thus, inhibition of the mitochondrial superoxide dismutase form, sod-2, in clk-1 mutants results in lifespan extension besides the increase in oxidative damage whereas inhibition of the cytosolic form, sod-1, led to an increase in the life span of daf-2 mutants although, in this case, accompanied by lower oxidative damage (Yang et al 2007). In addition, deletion of these sod genes in wild type worms does not produce decrease in lifespan although increase in oxidative damage was found (Yang et al 2007;Bennett et al 2014;Cabreiro et al 2011;Labunskyy et al 2014;Ren et al 2015;Schulz and Haynes 2015). These results imply that extension of longevity does not necessarily have to correlate with reduced ROS level in C. elegans.…”

“…Interestingly, the effect of overexpression of sod-1 on longevity seems to depend on the activation of the endoplasmic reticulum unfolded protein response (UPR) and not by reduction of oxidative stress that was even higher. The role of the induction of UPR in longevity is currently under controversy since some authors indicate that induction of mitochondrial UPR (mtUPR) is associated with stabilization of mitochondrial function and increase of longevity (Schulz and Haynes 2015), whereas others indicate that mtUPR signal is nor involved in aging in animals including C. elegans (Bennett et al 2014;Ren et al 2015). However, some authors have reported that the endoplasmic reticulumdependent UPR is associated with life span extension (Labunskyy et al 2014).…”

In vivo aspects of protein folding and quality control

“…These include the cytosolic stress response (128) and the unfolded protein response (UPR) pathways of the ER and mitochondria (129,130). The stress response of individual cell types and tissues is further coordinated at the organismal level by cellnonautonomous signaling mechanisms (4,131).…”

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

“…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). It is important that, recessive Clpp mutations have been identified in the human Perrault variant of ovarian failure and sensorineural hearing loss (Jenkinson et al., 2013), and global germline Clpp knockout mice display auditory deficits and complete female and male infertility, in addition to reduced pre/postnatal survival and marked ubiquitous growth retardation (Gispert et al., 2013).…”