Abstract
Aging and age-related neurodegeneration are both associated with the accumulation of unfolded and abnormally folded proteins, highlighting the importance of protein homeostasis (termed proteostasis) in maintaining organismal health. To this end, two cellular compartments with essential protein folding functions, the endoplasmic reticulum (ER) and the mitochondria, are equipped with unique protein stress responses, known as the ER unfolded protein response (UPRER) and the mitochondrial UPR (UPRmt), respectively. These organellar UPRs play roles in shaping the cellular responses to proteostatic stress that occurs in aging and age-related neurodegeneration. The loss of adaptive UPRER and UPRmt signaling potency with age contributes to a feed-forward cycle of increasing protein stress and cellular dysfunction. Likewise, UPRER and UPRmt signaling is often altered in age-related neurodegenerative diseases; however, whether these changes counteract or contribute to the disease pathology appears to be context dependent. Intriguingly, altering organellar UPR signaling in animal models can reduce the pathological consequences of aging and neurodegeneration which has prompted clinical investigations of UPR signaling modulators as therapeutics. Here, we review the physiology of both the UPRER and the UPRmt, discuss how UPRER and UPRmt signaling changes in the context of aging and neurodegeneration, and highlight therapeutic strategies targeting the UPRER and UPRmt that may improve human health.
Highlights
Maintaining protein homeostasis within cells is essential for cellular health, especially in post-mitotic cells such as neurons that cannot dilute the ill-effects of misfolded, unfolded, or aggregated proteins through cell division
Data from human post-mortem tissue and animal models suggest that both the unfolded protein response (UPRER) and the mitochondrial unfolded protein response (UPRmt) change significantly at older ages. Both the UPRER and the UPRmt lose adaptive signaling potency potentially leading to a detrimental state where the unfolded protein response (UPR) is unable to resolve the stresses brought about by age-related cellular dysfunction (Sheng et al, 2021)
For the UPRmt, it appears that activation through the activating transcription factor 5 (ATF5)-UPRmt and SIRT3-UPRmt promotes healthy aging and lifespan extension, if induced in juveniles. Whether activation of these arms of the UPRmt is sufficient to extend lifespan remains unclear due, in part, to the technical challenges of isolating UPRmt signaling from the inciting stressors and other activated parallel stress response pathways
Summary
Maintaining protein homeostasis (hereafter: proteostasis) within cells is essential for cellular health, especially in post-mitotic cells such as neurons that cannot dilute the ill-effects of misfolded, unfolded, or aggregated proteins through cell division. For invertebrates as well as mammals, the translational and epigenetic changes induced by the mitochondrial stress signaled through the ATF5-UPRmt result in (1) an upregulation of the expression of mitochondrial chaperones, proteases, protein importers, and ETC components; (2) a reduction in global protein translation in the cytosol; (3) a decrease in protein translation within mitochondria; and (4) a reprogramming of mitochondrial metabolism (Zhao, 2002; Yoneda et al, 2004; Aldridge et al, 2007; Baker et al, 2012; Nargund et al, 2012, 2015; Houtkooper et al, 2013; Gitschlag et al, 2016; Münch and Harper, 2016; Borch Jensen et al, 2018; Molenaars et al, 2020; Yuan et al, 2020) These effects reduce proteotoxic stress in the mitochondrial matrix by increasing protein folding and degradation capacity, reducing protein burden within the mitochondria, and shifting metabolic demand away from the mitochondria, presumably to allow for the restoration of proper ETC function. Induction of the UPRmt only during adulthood does not affect lifespan and may have detrimental effects, perhaps because of age-related epigenetic alterations that prevent access to UPRmt-induced genes (Dillin et al, 2002; Rea et al, 2007; Durieux et al, 2011; Labbadia and Morimoto, 2015; Conte et al, 2019)
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