scholarly journals UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import

2020 ◽  
Author(s):  
Tomer Shpilka ◽  
YunGuang Du ◽  
Qiyun Yang ◽  
Andrew Melber ◽  
Nandhitha U. Naresh ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Synthesis ◽  
Protein Import ◽  
Dependent Manner ◽  
Mitochondrial Network ◽  
Mitochondrial Import ◽  
Network Expansion ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

AbstractAs organisms develop, individual cells generate mitochondria to fulfill physiologic requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth and impacted by environmental cues. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS)1. Here, we demonstrate that ATFS-1 mediates an adaptable mitochondrial expansion program that is active throughout normal development. Developmental mitochondrial network expansion required the relatively inefficient MTS2 in ATFS-1, which allowed the transcription factor to be responsive to parameters that impact protein import capacity of the entire mitochondrial network. Increasing the strength of the ATFS-1 MTS impaired UPRmt activity throughout development due to increased accumulation within mitochondria. The insulin-like signaling-TORC13 and AMPK pathways affected UPRmt activation4,5 in a manner that correlated with protein synthesis. Manipulation to increase protein synthesis caused UPRmt activation. Alternatively, S6 kinase inhibition had the opposite effect due to increased mitochondrial accumulation of ATFS-1. However, ATFS-1 with a dysfunctional MTS6 constitutively increased UPRmt activity independent of TORC1 function. Lastly, expression of a single protein with a strong MTS, was sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPRmt activation. Mitochondrial network expansion is attenuated once ATFS-1 can be imported.

scholarly journals UPRmt scales mitochondrial network expansion with protein synthesis via mitochondrial import in Caenorhabditis elegans

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tomer Shpilka ◽  
YunGuang Du ◽  
Qiyuan Yang ◽  
Andrew Melber ◽  
Nandhitha Uma Naresh ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Synthesis ◽  
Caenorhabditis Elegans ◽  
Protein Import ◽  
Model Organism ◽  
Dependent Manner ◽  
Mitochondrial Network ◽  
Mitochondrial Import ◽  
Activity Increase ◽  
Network Expansion

AbstractAs organisms develop, individual cells generate mitochondria to fulfill physiological requirements. However, it remains unknown how mitochondrial network expansion is scaled to cell growth. The mitochondrial unfolded protein response (UPRmt) is a signaling pathway mediated by the transcription factor ATFS-1 which harbors a mitochondrial targeting sequence (MTS). Here, using the model organism Caenorhabditis elegans we demonstrate that ATFS-1 mediates an adaptable mitochondrial network expansion program that is active throughout normal development. Mitochondrial network expansion requires the relatively inefficient MTS in ATFS-1, which allows the transcription factor to be responsive to parameters that impact protein import capacity of the mitochondrial network. Increasing the strength of the ATFS-1 MTS impairs UPRmt activity by increasing accumulation within mitochondria. Manipulations of TORC1 activity increase or decrease ATFS-1 activity in a manner that correlates with protein synthesis. Lastly, expression of mitochondrial-targeted GFP is sufficient to expand the muscle cell mitochondrial network in an ATFS-1-dependent manner. We propose that mitochondrial network expansion during development is an emergent property of the synthesis of highly expressed mitochondrial proteins that exclude ATFS-1 from mitochondrial import, causing UPRmt activation.

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

2018 ◽  
Author(s):  
Yves T. Wang ◽  
Yunki Lim ◽  
Matthew N. McCall ◽  
Cole M. Haynes ◽  
Keith Nehrke ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Unfolded Protein Response ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Nuclear Targeting ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

ABSTRACTThe mitochondrial unfolded protein response (UPRmt)1 is a cytoprotective signaling pathway triggered by mitochondrial dysfunction. Activation of the UPRmt upregulates nuclear-encoded mitochondrial genes, including those for chaperones, proteases, and antioxidants, as well as glycolysis, to restore proteostasis and cell energetics. Activating transcription factor 5 (ATF5), a protein with both mitochondrial and nuclear targeting sequences, is proposed to mediate mammalian UPRmt signaling. Since proteostasis and bioenergetics are important in the response of organs such as the heart to injury, we hypothesized that pharmacologic UPRmt activation may be cardioprotective against ischemia-reperfusion (IR) injury and that such protection would require ATF5. Using a perfused heart IR injury model in wild-type and global Atf5−/− mice, we found that in-vivo administration of the UPRmt inducers oligomycin or doxycycline 6 h prior to ex-vivo IR injury was cardioprotective. Such protection was absent in hearts from Atf5−/− mice, and no protection was observed with acute ex-vivo cardiac administration of doxycycline. Loss of ATF5 also did not alter baseline IR injury (without UPRmt induction). Cardiac gene expression analysis by RNA-Seq revealed mild induction of numerous genes in an ATF5-dependent manner, which may be important for cardioprotection. Analysis of hearts by qPCR showed that oligomycin at 6 h significantly induced genes encoding ATF5 and several known UPRmt-linked proteins. We conclude that ATF5 is required for cardioprotection induced by drugs that activate the UPRmt.

scholarly journals Cardioprotection by the mitochondrial unfolded protein response requires ATF5

2019 ◽  
Vol 317 (2) ◽  
pp. H472-H478 ◽  
Author(s):  
Yves T. Wang ◽  
Yunki Lim ◽  
Matthew N. McCall ◽  
Kai-Ting Huang ◽  
Cole M. Haynes ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Unfolded Protein Response ◽  
Ex Vivo ◽  
Ischemia Reperfusion ◽  
Dependent Manner ◽  
Unfolded Protein ◽  
Activating Transcription Factor ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

The mitochondrial unfolded protein response (UPRmt) is a cytoprotective signaling pathway triggered by mitochondrial dysfunction. UPRmt activation upregulates chaperones, proteases, antioxidants, and glycolysis at the gene level to restore proteostasis and cell energetics. Activating transcription factor 5 (ATF5) is a proposed mediator of the mammalian UPRmt. Herein, we hypothesized pharmacological UPRmt activation may protect against cardiac ischemia-reperfusion (I/R) injury in an ATF5-dependent manner. Accordingly, in vivo administration of the UPRmt inducers oligomycin or doxycycline 6 h before ex vivo I/R injury (perfused heart) was cardioprotective in wild-type but not global Atf5−/− mice. Acute ex vivo UPRmt activation was not cardioprotective, and loss of ATF5 did not impact baseline I/R injury without UPRmt induction. In vivo UPRmt induction significantly upregulated many known UPRmt-linked genes (cardiac quantitative PCR and Western blot analysis), and RNA-Seq revealed an UPRmt-induced ATF5-dependent gene set, which may contribute to cardioprotection. This is the first in vivo proof of a role for ATF5 in the mammalian UPRmt and the first demonstration that UPRmt is a cardioprotective drug target. NEW & NOTEWORTHY Cardioprotection can be induced by drugs that activate the mitochondrial unfolded protein response (UPRmt). UPRmt protection is dependent on activating transcription factor 5 (ATF5). This is the first in vivo evidence for a role of ATF5 in the mammalian UPRmt.

Abstract 3760: Atherogenic Affects Of Arsenic: Role Of Endoplasmic Reticulum Stress And Unfolded Protein Response

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Petra Haberzettl ◽  
Elena Vladykovskaya ◽  
Oleg Barski ◽  
Srinivas Sithu ◽  
Stanley D’Souza ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Unfolded Protein Response ◽  
Atherosclerotic Lesion ◽  
The United States ◽  
Hazardous Substance ◽  
Dependent Manner ◽  
Lesion Formation ◽  
Chemical Chaperone ◽  
Unfolded Protein ◽  
Protein Response

Arsenic is a global water contaminant and EPA has listed arsenic as a high priority hazardous substance in the United States. Epidemiological studies suggest that chronic arsenic ingestion increases cardiovascular disease in humans, particularly, carotid atherosclerosis. However, mechanisms of arsenic-induced atherogenesis are unknown. We examined the effect of arsenic exposure on early lesion formation in apoE-null mice maintained on water supplemented with (0, 1, 5 and 50 ppm; 3–16 weeks of age) sodium arsenite. Arsenic, did not affect plasma cholesterol but decreased the triglycerides by 18±4 % (P<0.05). NMR analysis of the lipoproteins showed a significant decrease in the abundance of large VLDL particle (>60 nm diameter). Despite a significant decrease in plasma triglyceride, atherosclerotic lesion formation was significantly increased (2– 4 fold; P<0.05 for all doses) in the aortic sinus and the aortic arch of the arsenic-fed mice in a dose dependent manner. Immunohistochemical analysis showed significant increase in the accumulation of macrophages, expression of MCP-1 and unfolded protein response (UPR) dependent activating transcription factor (ATF)-4 and ATF3, in the lesions of arsenic (1ppm) exposed mice. In vitro , arsenic (5–25 μM), significantly increased the expression of ICAM-1, transmigration of differentiated monocytes and expression of the pro-inflammatory cytokine IL-8 in vascular endothelial cells (vEC). Arsenic, also increased the expression of ER-chaperones Grp 78, HERP and calnexin (2– 6 fold; P<0.01). Examination of the effect of arsenic on UPR showed that arsenic, induced the splicing of IRE-1 dependent, bZIP transcription factor XBP-1(alarm phase) and increased the phosphorylation of eIF2α (PERK mediated adaptive phase) by 3 fold (P<0.01) in vEC. Arsenic also induced the expression of the downstream effecter proteins of eIF2α-ATF3 (8 fold; P<0.01) and pro-apoptotic protein CHOP (4 fold; P<0.01) in vEC. Chemical chaperone, phenyl butyric acid (PBA), attenuated the arsenic-induced expression of ATF3 (>90%; P<0.001) and CHOP (>90%; P<0.001). These data suggest that ER-stress and UPR could exacerbate arsenic-induced vascular inflammation and promote atherogenesis.

scholarly journals Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30

2019 ◽  
Author(s):  
Yasmine J. Liu ◽  
Rebecca L. McIntyre ◽  
Georges E. Janssens ◽  
Evan G. Williams ◽  
Jiayi Lan ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Mitochondrial Network ◽  
Mitochondrial Translation ◽  
C Elegans ◽  
Form And Function ◽  
Unfolded Protein ◽  
Lysosome Biogenesis ◽  
And Function ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

AbstractMitochondrial form and function, such as translation, are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, which is accompanied by a fragmented mitochondrial network. However, the causality between mitochondrial translation and morphology in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by either blocking fission or fusion synergizes with the reduced mitochondrial translation to substantially prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous abrogation of fission and fusion reverses the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic connections between mitochondrial translation and dynamics in regulating longevity.SUMMARYMitochondrial form and function are intimately intertwined. Liu et al. find the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan. This synergy is dependent on the induction of lysosome biogenesis through the nuclear localization of HLH-30.

scholarly journals Mitochondrial translation and dynamics synergistically extend lifespan in C. elegans through HLH-30

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Yasmine J. Liu ◽  
Rebecca L. McIntyre ◽  
Georges E. Janssens ◽  
Evan G. Williams ◽  
Jiayi Lan ◽  
...  
Keyword(s):  
Mitochondrial Dynamics ◽  
Mitochondrial Network ◽  
Mitochondrial Translation ◽  
C Elegans ◽  
Form And Function ◽  
Unfolded Protein ◽  
Lysosome Biogenesis ◽  
And Function ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Mitochondrial form and function are closely interlinked in homeostasis and aging. Inhibiting mitochondrial translation is known to increase lifespan in C. elegans, and is accompanied by a fragmented mitochondrial network. However, whether this link between mitochondrial translation and morphology is causal in longevity remains uncharacterized. Here, we show in C. elegans that disrupting mitochondrial network homeostasis by blocking fission or fusion synergizes with reduced mitochondrial translation to prolong lifespan and stimulate stress response such as the mitochondrial unfolded protein response, UPRMT. Conversely, immobilizing the mitochondrial network through a simultaneous disruption of fission and fusion abrogates the lifespan increase induced by mitochondrial translation inhibition. Furthermore, we find that the synergistic effect of inhibiting both mitochondrial translation and dynamics on lifespan, despite stimulating UPRMT, does not require it. Instead, this lifespan-extending synergy is exclusively dependent on the lysosome biogenesis and autophagy transcription factor HLH-30/TFEB. Altogether, our study reveals the mechanistic crosstalk between mitochondrial translation, mitochondrial dynamics, and lysosomal signaling in regulating longevity.

scholarly journals Mitochondrial translation inhibition triggers ATF4 activation, leading to integrated stress response but not to mitochondrial unfolded protein response

2020 ◽  
Vol 40 (11) ◽  
Author(s):  
Katsuhiko Sasaki ◽  
Takeshi Uchiumi ◽  
Takahiro Toshima ◽  
Mikako Yagi ◽  
Yura Do ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Stress Response ◽  
Unfolded Protein Response ◽  
Integrated Stress Response ◽  
Mitochondrial Translation ◽  
Translation Inhibition ◽  
Unfolded Protein ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Abstract Mitochondrial–nuclear communication, known as retrograde signaling, is important for regulating nuclear gene expression in response to mitochondrial dysfunction. Previously, we have found that p32/C1qbp-deficient mice, which have a mitochondrial translation defect, show endoplasmic reticulum (ER) stress response and integrated stress response (ISR) gene expression in the heart and brain. However, the mechanism by which mitochondrial translation inhibition elicits these responses is not clear. Among the transcription factors that respond to mitochondrial stress, activating transcription factor 4 (ATF4) is a key transcription factor in the ISR. Herein, chloramphenicol (CAP), which inhibits mitochondrial DNA (mtDNA)-encoded protein expression, induced eukaryotic initiation factor 2 α subunit (eIF2α) phosphorylation and ATF4 induction, leading to ISR gene expression. However, the expression of the mitochondrial unfolded protein response (mtUPR) genes, which has been shown in Caenorhabditis elegans, was not induced. Short hairpin RNA-based knockdown of ATF4 markedly inhibited the CAP-induced ISR gene expression. We also observed by ChIP analysis that induced ATF4 bound to the promoter region of several ISR genes, suggesting that mitochondrial translation inhibition induces ISR gene expression through ATF4 activation. In the present study, we showed that mitochondrial translation inhibition induced the ISR through ATF4 activation rather than the mtUPR.

Abstract 16554: Sphingosine-1-Phosphate Activates the Mitochondrial Unfolded Protein Response in the Pulmonary Vasculature

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Angelia D Lockett ◽  
Grace Vlasak ◽  
Viswanathan Natarajan ◽  
Roberto F MacHado
Keyword(s):  
Unfolded Protein Response ◽  
Vascular Remodeling ◽  
Dependent Manner ◽  
Mitofusin 2 ◽  
Unfolded Protein ◽  
Cell Extracts ◽  
Sphingosine 1 Phosphate ◽  
Pulmonary Arterial ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

Introduction: Aberrant activation of pathways that promote pulmonary arterial smooth muscle (PASMC) and endothelial cell (PAEC) proliferation causes vascular remodeling and increased vascular resistance that leads to the deadly disease Pulmonary Arterial Hypertension (PAH). Sphingosine-1-phosphate (S1P) induces PASMCs proliferation and disruption of its signaling mitigates vascular remodeling and PAH. Mitochondria regulate proliferation and can promote or inhibit it in a signal dependent manner. The mitochondrial unfolded protein response (UPR mt ) is a mechanism by which mitochondria preserve cell survival due to stress. Mitochondria are important mediators of PASMC proliferation and PAH development as both mitochondrial (mt) fission and aerobic glycolysis contribute to disease progression. Studies in C. elegans suggest a link between regulation of mt fission and activation of the UPR mt as suppression of fission leads to S1P dependent activation of the UPR mt . Hypothesis: We hypothesized that S1P stimulation leads to activation of the UPR mt to promote proliferation of hPASMCs and hPAECs. Methods: hPASMCs were stimulated with S1P (1 μM) for up to 24h. Cell extracts were analyzed by immunoblotting for proteins (eIF2α, ATF-5, HSP70 and Lonp1) that regulate the UPR mt . Mitochondrial dynamics was assessed by immunoblotting or immunofluorescence for mediators of fission (Drp-1) and fusion (mitofusin-2). SPHK1, the lipid kinase that catalyzes S1P generation, was overexpressed in hPAECs followed by immunoblotting for UPR mt and mt fission activation. PCNA expression was assessed to measure cell proliferation. Results: S1P stimulation of hPASMCs enhanced proliferation and caused rapid and sustained activation of the UPR mt as phosphorylation of eIF2α and expression of ATF-5 and HSP70 were increased. S1P also enhanced mt fission in hPASMCs as Drp-1 phosphorylation was increased concomitant with decreased mitofusin-2 expression. Overexpression of SPHK1 in hPAECs increased proliferation and activation of both the UPR mt and mt fission. Conclusions: S1P promotes functional and phenotypic changes of mitochondria that leads to activation of pathways that promote PASMC and PAEC proliferation which could contribute to vascular remodeling in PAH.

Sign in / Sign up

Export Citation Format

Share Document