A Futile Battle? Protein Quality Control and the Stress of Aging

Higuchi‐Sanabria, Ryo; Frankino, Phillip A.; Paul, Joel R.; Tronnes, Sarah U.; Dillin, Andrew

doi:10.1016/j.devcel.2017.12.020

Cited by 130 publications

(118 citation statements)

References 317 publications

(352 reference statements)

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…CEBPb, ATF4, and CHOP are also key activators of the mitochondrial unfolded protein response (mtUPR) (Higuchi-Sanabria et al, 2018;Moehle et al, 2018); however, we did not observe significant upregulation of mitochondrial proteases in the Mrps12 ep/ep mice, perhaps due to a simultaneous induction of systems that stabilize mitochondrial respiratory complexes, as we observed in these mice at 10 weeks of age. We and others have previously observed increased ATF4 and CHOP in mouse models with impaired mitochondrial translation (Rackham et al, 2016;Seiferling et al, 2016;Perks et al, 2018), and impaired mitochondrial translation can induce mtUPR in worms and mammalian cell culture (Houtkooper et al, 2013).…”

Section: Of 19contrasting

confidence: 73%

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

et al. 2019

View full text Add to dashboard Cite

Translation fidelity is crucial for prokaryotes and eukaryotic nuclear‐encoded proteins; however, little is known about the role of mistranslation in mitochondria and its potential effects on metabolism. We generated yeast and mouse models with error‐prone and hyper‐accurate mitochondrial translation, and found that translation rate is more important than translational accuracy for cell function in mammals. Specifically, we found that mitochondrial mistranslation causes reduced overall mitochondrial translation and respiratory complex assembly rates. In mammals, this effect is compensated for by increased mitochondrial protein stability and upregulation of the citric acid cycle. Moreover, this induced mitochondrial stress signaling, which enables the recovery of mitochondrial translation via mitochondrial biogenesis, telomerase expression, and cell proliferation, and thereby normalizes metabolism. Conversely, we show that increased fidelity of mitochondrial translation reduces the rate of protein synthesis without eliciting a mitochondrial stress response. Consequently, the rate of translation cannot be recovered and this leads to dilated cardiomyopathy in mice. In summary, our findings reveal mammalian‐specific signaling pathways that respond to changes in the fidelity of mitochondrial protein synthesis and affect metabolism.

show abstract

Section: Of 19contrasting

confidence: 73%

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

et al. 2019

View full text Add to dashboard Cite

show abstract

“…Thus, the role of AMPK (i.e., AAK‐1 and AAK‐2) signaling in DR‐induced longevity may be broader than previously thought. As aging is often linked to accumulations of damaged proteins, maintaining protein homeostasis (or proteostasis) is critical for longevity regulation (Higuchi‐Sanabria, Frankino, Paul, Tronnes, & Dillin, 2018). Here, our findings suggest that DR may activate the AMPK‐eE2K axis to regulate proteostasis and consequently the rate of aging via inhibiting translation and elevating SG formation.…”

Section: Discussionmentioning

confidence: 99%

AMPK‐mediated formation of stress granules is required for dietary restriction‐induced longevity in Caenorhabditis elegans

Kuo¹,

You²,

Jian³

et al. 2020

Aging Cell

View full text Add to dashboard Cite

Stress granules (SGs) are nonmembranous organelles that are dynamically assembled and disassembled in response to various stressors. Under stressed conditions, polyadenylated mRNAs and translation factors are sequestrated in SGs to promote global repression of protein synthesis. It has been previously demonstrated that SG formation enhances cell survival and stress resistance. However, the physiological role of SGs in organismal aging and longevity regulation remains unclear. In this study, we used TIAR‐1::GFP and GTBP‐1::GFP as markers to monitor the formation of SGs in Caenorhabditis elegans. We found that, in addition to acute heat stress, SG formation could also be triggered by dietary changes, such as starvation and dietary restriction (DR). We found that HSF‐1 is required for the SG formation in response to acute heat shock and starvation but not DR, whereas the AMPK‐eEF2K signaling is required for starvation and DR‐induced SG formation but not heat shock. Moreover, our data suggest that this AMPK‐eEF2K pathway‐mediated SG formation is required for lifespan extension by DR, but dispensable for the longevity by reduced insulin/IGF‐1 signaling. Collectively, our findings unveil a novel role of SG formation in DR‐induced longevity.

show abstract

“…Mitochondrial electron transport chain (ETC) perturbation via the downregulation of a complex IV subunit (cco-1) has been extensively described to dramatically increase longevity (Higuchi-Sanabria et al, 2018a;Moehle et al, 2018). Similar to neuronal xbp-1s animals, lipids are significantly decreased in cco-1 RNAi animals (Extended Data Fig.…”

Section: A Lipophagy Complex Mediates Cerm Formation and Lipid Turnovmentioning

confidence: 99%

“…lifespan, stress resistance). Work with C. elegans has shown that its cells become less capable in protein folding and also less able to induce stress responses to proteotoxicity with advanced age (Ben-Zvi et al, 2009;Brown and Naidoo, 2012;Dillin et al, 2002aDillin et al, , 2002bDurieux et al, 2011;Higuchi-Sanabria et al, 2018a;Taylor and Dillin, 2013). Interestingly, overexpression (OE) of the spliced version of xbp-1 (xbp-1-s) specifically in neurons, extends organismal lifespan and increases ER stress tolerance in a cell non-autonomous manner (Taylor and Dillin, 2013).…”

mentioning

confidence: 99%

A non-canonical arm of UPR^ER mediates longevity through ER remodeling and lipophagy

Danièle

Higuchi‐Sanabria

Vignesh

et al. 2018

Preprint

Self Cite

View full text Add to dashboard Cite

Longevity is dictated by a combination of environmental and genetic factors. One of the key mechanisms implicated in regulating lifespan extension is the ability to induce protein chaperones to promote protein homeostasis. However, it is unclear whether protein chaperones exclusively regulate longevity. Previous work has shown that activating the unfolded protein response of the endoplasmic reticulum (UPR ER ) in neurons can signal peripheral tissues to promote chaperone expression, thus enhancing organismal stress resistance and extending lifespan. Here, we find that this activation not only promotes chaperones, but facilitates a dramatic restructuring of ER morphology in intestinal cells. This restructuring, which includes depletion of lipid droplets, ER expansion, and ER tubulation, depends of lipophagy. Surprisingly, we find that lipophagy is required for lifespan extension and is completely independent of chaperone function. Therefore, UPR induction in neurons triggers two distinct programs in the periphery: the canonical arm through protein chaperones, and a non-canonical mechanism through lipid depletion. In summary, our study identifies lipophagy as an integral component of UPR ER -induced longevity. MAINLife presents a myriad of challenges, stressors, and environmental shifts to which cells must adapt in order to survive and thrive. The homeostatic regulation of protein folding (proteostasis), which is monitored in specific subcellular compartments (the endoplasmic reticulum (ER), mitochondria, cytosol) is an integral player in stress resistance and longevity. The ER, in particular, is a central regulator of stress monitoring since it controls (1) nearly a third of the cell's proteins, (2) provides an internal medium and transponder for lipid homeostasis and cell signaling, and (3) communicates directly with all other organelles to maintain cellular secretion.

show abstract

A Futile Battle? Protein Quality Control and the Stress of Aging

Cited by 130 publications

References 317 publications

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

AMPK‐mediated formation of stress granules is required for dietary restriction‐induced longevity in Caenorhabditis elegans

A non-canonical arm of UPR^ER mediates longevity through ER remodeling and lipophagy

Contact Info

Product

Resources

About

A Futile Battle? Protein Quality Control and the Stress of Aging

Cited by 130 publications

References 317 publications

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation

AMPK‐mediated formation of stress granules is required for dietary restriction‐induced longevity in Caenorhabditis elegans

A non-canonical arm of UPRER mediates longevity through ER remodeling and lipophagy

Contact Info

Product

Resources

About

A non-canonical arm of UPR^ER mediates longevity through ER remodeling and lipophagy