Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyond

Haynes, Cole M.; Fiorese, Christopher J.; Lin, Yifan

doi:10.1016/j.tcb.2013.02.002

Cited by 172 publications

(142 citation statements)

References 84 publications

(132 reference statements)

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“…the destruction of dysfunctional mitochondria by autophagy (Kim et al, 2007). Interestingly, mitophagy is believed to be part of a more complex response, the mitochondrial unfolded-protein response, which is a stress response triggered by the accumulation of unfolded or misfolded proteins in the mitochondrial matrix and subsequent activation of molecular chaperones such as heat shock protein 60 (Hsp60) and mitochondrial Hsp70 (Haynes et al, 2013;Jovaisaite et al, 2014). Even though little information is available about Hsp60 in fish (but see Buckley et al, 2006), it has been demonstrated that after acute heat stress (Currie et al, 2000;Deane and Woo, 2005) or during mild warming (Logan and Somero, 2011) the transcript abundance of Hsp70 is initially increased but then decreases with further acclimation (Currie et al, 2000;Deane and Woo, 2005).…”

Section: Discussionmentioning

confidence: 99%

Dynamic changes in cardiac mitochondrial metabolism during warm acclimation in rainbow trout

Pichaud

Ekström

Hellgren

et al. 2017

Journal of Experimental Biology

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Although the mitochondrial metabolism responses to warm acclimation have been widely studied in fish, the time course of this process is less understood. Here, we characterized the changes of rainbow trout (Oncorhynchus mykiss) cardiac mitochondrial metabolism during acute warming from 10 to 16°C, and during the subsequent warm acclimation for 39 days. We repeatedly measured mitochondrial oxygen consumption in cardiac permeabilized fibers and the functional integrity of mitochondria (i.e. mitochondrial coupling and cytochrome c effect) at two assay temperatures (10 and 16°C), as well as the activities of citrate synthase (CS) and lactate dehydrogenase (LDH) at room temperature. LDH and CS activities significantly increased between day 0 (10°C acclimated fish) and day 1 (acute warming to 16°C) while mitochondrial oxygen consumption measured at respective in vivo temperatures did not change. Enzymatic activities and mitochondrial oxygen consumption rates significantly decreased by day 2, and remained stable during warm acclimation (days 2-39). The decrease in rates of oxygen between day 0 and day 1 coincided with an increased cytochrome c effect and a decreased mitochondrial coupling, suggesting a structural/ functional impairment of mitochondria during acute warming. We suggest that after 2 days of warm acclimation, a new homeostasis is reached, which may involve the removal of dysfunctional mitochondria. Interestingly, from day 2 onwards, there was a lack of differences in mitochondrial oxygen consumption rates between the assay temperatures, suggesting that warm acclimation reduces the acute thermal sensitivity of mitochondria. This study provides significant knowledge on the thermal sensitivity of cardiac mitochondria that is essential to delineate the contribution of cellular processes to warm acclimation.

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Section: Discussionmentioning

confidence: 99%

Dynamic changes in cardiac mitochondrial metabolism during warm acclimation in rainbow trout

Pichaud

Ekström

Hellgren

et al. 2017

Journal of Experimental Biology

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“…A universally conserved trigger for HS responses is the accumulation of unfolded proteins. In eukaryotes, these are known to be sensed in the cytosol, the endoplasmic reticulum (ER), and mitochondria and signaled to the nucleus to initiate appropriate transcriptional responses (Voellmy and Boellmann, 2007;Walter and Ron, 2011;Haynes et al, 2013). Recent work suggested that an unfolded protein response also exists in the chloroplast (Yu et al, 2012;Schmollinger et al, 2013;Ramundo et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Systems-Wide Analysis of Acclimation Responses to Long-Term Heat Stress and Recovery in the Photosynthetic Model OrganismChlamydomonas reinhardtii

et al. 2014

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We applied a top-down systems biology approach to understand how Chlamydomonas reinhardtii acclimates to long-term heat stress (HS) and recovers from it. For this, we shifted cells from 25 to 42°C for 24 h and back to 25°C for ‡8 h and monitored abundances of 1856 proteins/protein groups, 99 polar and 185 lipophilic metabolites, and cytological and photosynthesis parameters. Our data indicate that acclimation of Chlamydomonas to long-term HS consists of a temporally ordered, orchestrated implementation of response elements at various system levels. These comprise (1) cell cycle arrest; (2) catabolism of larger molecules to generate compounds with roles in stress protection; (3) accumulation of molecular chaperones to restore protein homeostasis together with compatible solutes; (4) redirection of photosynthetic energy and reducing power from the Calvin cycle to the de novo synthesis of saturated fatty acids to replace polyunsaturated ones in membrane lipids, which are deposited in lipid bodies; and (5) when sinks for photosynthetic energy and reducing power are depleted, resumption of Calvin cycle activity associated with increased photorespiration, accumulation of reactive oxygen species scavengers, and throttling of linear electron flow by antenna uncoupling. During recovery from HS, cells appear to focus on processes allowing rapid resumption of growth rather than restoring pre-HS conditions.

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“…These pathways are regulated by the heat shock response (HSR), the unfolded protein response (UPR) of the endoplasmic reticulum (ER), the mitochondrial UPR (UPR mt ), and the oxidative stress response (OxSR). Gene induction through these pathways is coordinated by the transcription factors HSF-1 (HSR), XBP-1 and ATF-6 (UPR ER ), ATFS-1 (UPR mt ), SKN-1/NRF-2 (OxSR), and Daf-16/FOXO3A (HSR and OxSR) [35][36][37][38][39][40]. We propose that these stress pathways represent an integrated stress network that provides robust protection against a wide range of acute and chronic stress conditions and therefore are essential modifiers of aging and disease [14,[41][42][43][44].…”

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confidence: 99%

Proteostasis and longevity: when does aging really begin?

Labbadia¹,

Morimoto²

2014

F1000Prime Rep

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Aging is a complex process regulated by multiple cellular pathways, including the proteostasis network. The proteostasis network consists of molecular chaperones, stress-response transcription factors, and protein degradation machines that sense and respond to proteotoxic stress and protein misfolding to ensure cell viability. A loss of proteostasis is associated with aging and age-related disorders in diverse model systems, moreover, genetic or pharmacological enhancement of the proteostasis network has been shown to extend lifespan and suppress age-related disease. However, our understanding of the relationship between aging, proteostasis, and the proteostasis network remains unclear. Here, we propose, from studies in Caenorhabditis elegans, that proteostasis collapse is not gradual but rather a sudden and early life event that triggers proteome mismanagement, thereby affecting a multitude of downstream processes. Furthermore, we propose that this phenomenon is not stochastic but is instead a programmed re-modeling of the proteostasis network that may be conserved in other species. As such, we postulate that changes in the proteostasis network may be one of the earliest events dictating healthy aging in metazoans. Aging, proteome integrity, and the proteostasis networkAging is inextricably linked to the world around us and regularly pervades everyday life. Despite this, why organisms age remains a complex mystery that if understood could have profound implications for the quality of human health. While the physiological decline associated with old age is easily recognizable, the mechanisms that determine aging are poorly understood; however, widescale loss of protein homeostasis (proteostasis) is proposed to be one of the "primary hallmarks of aging" [1].Protein aggregation is associated with many age-related disorders, and increased protein oxidation, mislocalization, and aggregation are observed in aged organisms [2][3][4][5][6][7]. Intuitively, these findings can be explained by a gradual decline in protein biosynthetic and quality control pathways and a progressive accumulation of protein damage. However, recent findings in Caenorhabditis elegans challenge this view, suggesting that a decline in proteome integrity may be the result of early programmed events rather than the consequence of a random and gradual accrual of molecular damage.Proteostasis is maintained by the proteostasis network (PN), a system of molecular chaperones, protein degradation machines, and stress response pathways that act alone or together in various subnetworks to sense and respond to protein misfolding in all cellular compartments [8]. This amalgamation of constitutive and inducible quality control mechanisms is central to the identity and health of the proteome [8]. Given the importance of the proteome to cell function, it is salient to ask, what is the relationship between proteostasis and aging? Attempts to address this in C. elegans have yielded a surprising and consistent result; a pronounced, widespread decline in p...

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Evaluating and responding to mitochondrial dysfunction: the mitochondrial unfolded-protein response and beyond

Cited by 172 publications

References 84 publications

Dynamic changes in cardiac mitochondrial metabolism during warm acclimation in rainbow trout

Dynamic changes in cardiac mitochondrial metabolism during warm acclimation in rainbow trout

Systems-Wide Analysis of Acclimation Responses to Long-Term Heat Stress and Recovery in the Photosynthetic Model OrganismChlamydomonas reinhardtii

Proteostasis and longevity: when does aging really begin?

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