The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans

Peña, Salvador; Sherman, Teresa; Brookes, Paul S.; Nehrke, Keith

doi:10.1371/journal.pone.0159989

Cited by 34 publications

(34 citation statements)

References 54 publications

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“…Little information about the impact of URPmt is described in the context of heart diseases. Acute ischemia/hypoxia-reperfusion induces UPRmt in C. elegans [39] or endothelial cells [40] and can be a protective response. However, loss of the mitochondrial aspartyl tRNA-synthetase encoding gene DARS2 in mice results in dysregulation of mitochondrial translation and strong cardiomyopathy associated with an increase of UPRmt markers [41].…”

Section: Mitochondrial Quality Controlmentioning

confidence: 99%

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

Gottlieb¹,

Thomas²

2017

Curr Pathobiol Rep

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PURPOSE OF REVIEW Mitochondrial homeostasis and quality control are essential to maintenance of cardiac function and a disruption of this pathway can lead to deleterious cardiac consequences. RECENT FINDINGS Mitochondrial quality control has been described as a major homeostatic mechanism in cell. Recent studies highlighted that an impairment of mitochondrial quality control in different cell or mouse models is linked to cardiac dysfunction. Moreover, some conditions as aging, genetic mutations or obesity have been associated with mitochondrial quality control alteration leading to an accumulation of damaged mitochondria responsible for increased production of reactive oxygen species, metabolic inflexibility, and inflammation, all of which can have sustained effects on cardiac cell function and even cell death. SUMMARY In this review, we describe the major mechanisms of mitochondrial quality control, factors that can impair mitochondrial quality control, and the consequences of disrupted mitochondrial quality control.

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Section: Mitochondrial Quality Controlmentioning

confidence: 99%

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

Gottlieb¹,

Thomas²

2017

Curr Pathobiol Rep

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“…Our data demonstrate that transient loss of PMF during 84 preconditioning is necessary and sufficient for resistance to hypoxia. By probing the 85 evolutionarily conserved hypoxia adaptation response (Pena, Sherman et al, 2016, Wang, Lim 86 et al, 2019, Wojtovich, Nadtochiy et al, 2012b, Wojtovich, Nadtochiy et al, 2013, we show that 87 tools like mtON allow precise determination of cause and effect in physiologic models. 88 89 RESULTS & DISCUSSION 90 Light-activated proton pump mitochondria-ON (mtON) is expressed in mitochondria.…”

mentioning

confidence: 77%

Controlling the Mitochondrial Protonmotive Force with Light to Impact Cellular Stress Resistance

Berry

Trewin

Milliken

et al. 2019

Preprint

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28Mitochondrial respiration generates an electrochemical proton gradient across the mitochondrial 29 inner membrane called the protonmotive force (PMF) to drive diverse functions and make ATP. 30 Current techniques to manipulate the PMF are limited to its dissipation; there is no precise, 31 reversible method to increase the PMF. To address this issue, we used an optogenetic 32 approach and engineered a mitochondria-targeted light-activated proton pumping protein we 33 called mitochondria-ON (mtON) to selectively increase the PMF. Here, mtON increased the 34 PMF light dose-dependently, supported ATP synthesis, increased resistance to mitochondrial 35 toxins, and modulated energy-sensing behavior in Caenorhabditis elegans. Moreover, transient 36 mtON activation during hypoxia prevented the well-characterized adaptive response of hypoxic 37 preconditioning. Our novel optogenetic approach demonstrated that a decreased PMF is both 38 necessary and sufficient for hypoxia-stimulated stress resistance. Our results show that 39 optogenetic manipulation of the PMF is a powerful tool to modulate metabolic and cell signaling 40 outcomes. 41 42 76organism Leptosphaeria maculans (Chow et al., 2010, Waschuk, Bezerra et al., 2005 to 77 3 mitochondria and selectively increase the PMF. We call this optogenetic tool mitochondria-ON 78 (mtON) due to its ability to mimic the proton pumping activity of the ETC in response to light, 79 independent of oxygen or substrate availability. 80 We validated mtON using the well-characterized genetic model organism, C. elegans 81 (Butler, Ventura et al., 2010, Dingley et al., 2010, Tsang & Lemire, 2003. Using hypoxia and 82 reoxygenation, we tested the hypothesis that hypoxia adaptation through preconditioning 83 requires a decreased PMF. Our data demonstrate that transient loss of PMF during 84 preconditioning is necessary and sufficient for resistance to hypoxia. By probing the 85 evolutionarily conserved hypoxia adaptation response (Pena, Sherman et al., 2016, Wang, Lim 86 et al., 2019, Wojtovich, Nadtochiy et al., 2012b, Wojtovich, Nadtochiy et al., 2013, we show that 87 tools like mtON allow precise determination of cause and effect in physiologic models. 88 89 RESULTS & DISCUSSION 90 Light-activated proton pump mitochondria-ON (mtON) is expressed in mitochondria. 91 Using a ubiquitously-expressed gene promoter (Peft-3), we directed expression of a 92 light-activated proton pump to the mitochondrial IM in C. elegans. Mitochondrial localization was 93 achieved by fusion of the proton pump to an N-terminal mitochondrial targeting sequence of the 94 IMMT1 protein (Fischer, Igoudjil et al., 2011, John, Shang et al., 2005 in an orientation that 95 allows proton pumping from the mitochondrial matrix towards the intermembrane space to 96 increase the PMF in response to light (Fig. 1A). Using a C-terminal GFP fusion for subcellular 97 visualization, and MitoTracker TM CMXRos, we observed overlap of green and red fluorescence 98 in C. elegans tissues, indicating the intended mitochondrial...

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“…The targets of UPR mt signaling include glycolysis, chaperones, proteases, and antioxidants (6). Accordingly, we previously showed that UPR mt induction was protective against anoxiareoxygenation in C. elegans (17). Herein we hypothesized that induction of an ATF5-dependent UPR mt may be cardioprotective.…”

mentioning

confidence: 94%

Cardioprotection by the mitochondrial unfolded protein response (UPR^mt) is mediated by activating transcription factor 5 (ATF5)

Wang

Lim

McCall

et al. 2018

Preprint

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The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans

Cited by 34 publications

References 54 publications

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

Controlling the Mitochondrial Protonmotive Force with Light to Impact Cellular Stress Resistance

Cardioprotection by the mitochondrial unfolded protein response (UPR^mt) is mediated by activating transcription factor 5 (ATF5)

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The Mitochondrial Unfolded Protein Response Protects against Anoxia in Caenorhabditis elegans

Cited by 34 publications

References 54 publications

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

Mitophagy and Mitochondrial Quality Control Mechanisms in the Heart

Controlling the Mitochondrial Protonmotive Force with Light to Impact Cellular Stress Resistance

Cardioprotection by the mitochondrial unfolded protein response (UPRmt) is mediated by activating transcription factor 5 (ATF5)

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Cardioprotection by the mitochondrial unfolded protein response (UPR^mt) is mediated by activating transcription factor 5 (ATF5)