Mitochondrial Proteostasis in the Control of Aging and Longevity

Abstract

Mitochondria play a central role in the aging process. Studies in model organisms have started to integrate mitochondrial effects on aging with the maintenance of protein homeostasis. These findings center on the mitochondrial unfolded protein response (UPRmt), which has been implicated in lifespan extension in worms, flies and mice, suggesting a conserved role for in the long-term maintenance of cellular homeostasis. Here, we review current knowledge of the UPRmt and discuss its integration with cellular pathways known to regulate lifespan. We highlight how insight into the UPRmt is revolutionizing our understanding of mitochondrial lifespan extension and of the aging process.

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

“…These pathways sense unfolded protein stress in a compartment‐specific manner, and signal to the nucleus for induction of the expression of unfolded protein response (UPR) genes, which are essential for proteostasis (Schinzel & Dillin, 2015). Mitochondrial unfolded protein response (mtUPR) is activated in response to a variety of mitochondrial stress factors including accumulation of unfolded proteins in the mitochondrial matrix (Rath et al., 2012), imbalance between mitochondrial DNA (mtDNA)‐encoded and nuclear‐encoded electron transport chain (ETC) components (Nargund, Pellegrino, Fiorese, Baker & Haynes, 2012; Yoneda et al., 2004), and perturbation of mitochondrial physiology through inhibition of ETC function or accumulation of reactive oxygen species (ROS) (Nargund et al., 2012; Yoneda et al., 2004), and ensures mitochondrial proteostasis by inducing a vigorous transcriptional response that promotes folding, limits import, and reduces translation of mitochondrial proteins (reviewed in Hill & Van Remmen, 2014; Jensen & Jasper, 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). 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).…”

Prolonged Fasting Identifies Heat Shock Protein 10 as a Sirtuin 3 Substrate

“…Although a component of mitochondrial quality control involves mitochondrial protein folding, whether this homeostatic program is directly modified and/or regulated by the acetyl posttranslational modification appears to not have been well characterized (36). In this study, we show that mitochondrial protein folding is modified by acetylation and that Hsp10 is a direct SIRT3 deacetylase substrate.…”

Caenorhabditis elegans as a research tool to study mitochondrial diseases associated with defects in tRNA modification

“…Por otra parte, la disminución de los niveles estacionarios de la proteína NUO-2, codificada por el genoma nuclear, en los mutantes mtcu-1 y mtcu-2 sugiere que hay una alteración en la traducción o el ensamblaje de algunas de las subunidades del complejo I. Como consecuencia, la pérdida de la homeostasis del proteoma mitocondrial (por acumulación de proteínas mal plegadas o de mala calidad, por degradación de proteínas que no llegan a ensamblarse al haber déficit de algunas codificadas por el mtDNA, o por degradación de proteínas intramitocondriales solubles, por ejemplo del ciclo de Krebs, a consecuencia de los cambios en el metabolismo mitocondrial promovidos por la alteración del funcionamiento del sistema OXPHOS) podría aumentar la proteostasis mitocondrial y los niveles de chaperonas mitocondriales, es decir, podría activar el mecanismo conocido como UPR mt (Haynes et al 2007;Taylor and Dillin 2011;Jensen and Jasper 2014). De hecho, en células humanas o murinas deficitarias en MTO1…”

“…Curiosamente, el silenciamiento de aak-1 en el doble mutante mtcu-2;mttu-1 parece tener un aumento mayor que en la cepa salvaje (***pvalor=0,0001), sugiriendo que en este doble mutante pueden estar actuando simultáneamente una ruta de envejecimiento activada por el silenciamiento de aak-1 pero independiente de la inactivación de mtcu-2 y mttu-1 y otra ruta dependiente de la inactivación de estos genes que está favorecida por el silenciamiento de aak-1 (figura R31A). Por otra parte, el silenciamiento de aak-2 en la cepa salvaje aumenta discretamente la longevidad a 25 o C (figura R31B), lo que contrasta con La mitocondria puede también regular la longevidad de C. elegans a través de la respuesta UPR mt pues se ha observado que, paradójicamente, la disfunción mitocondrial extiende la longevidad (Jensen and Jasper 2014). A este respecto, se ha sugerido que la activación de UPR mt tendría efectos protectores que redundarían en el beneficio de la longevidad.…”