Compromised Mitochondrial Protein Import Acts as a Signal for UPRmt

Rolland, Stéphane G.; Schneid, Sandra; Schwarz, Melanie; Rackles, Elisabeth; Fischer, Christian; Haeussler, Simon; Regmi, Saroj G.; Yeroslaviz, Assa; Habermann, Bianca; Mokranjac, Dejana; Lambie, Eric J.; Conradt, Barbara

doi:10.1016/j.celrep.2019.07.049

Cited by 131 publications

(116 citation statements)

References 53 publications

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“…As a positive control, we used animals carrying a lf mutation of the gene spg-7 AFG3L2 (spg-7(ad2249)), which encodes a mitochondrial metalloprotease required for mitochondrial function [41]. The zcIs13 transgene shows very low baseline expression in wild-type animals and is widely used to monitor UPR mt in C. elegans [7,[9][10][11][12][13][14][42][43][44]. In the case of fzo-1(tm1133) animals, for example, its expression is induced more than 15-fold (S1C Fig).…”

Section: Resultsmentioning

confidence: 99%

“…Since we did not see a change in mitochondrial morphology in fzo-1(tm1133) animals upon ESCRT(RNAi), we tested whether it affects mitochondrial membrane potential. Therefore, we stained larvae with TMRE (Tetramethylrhodamine ethyl ester), a membrane potential dependent dye that is commonly used in C. elegans to measure mitochondrial membrane potential in hypodermal cells [10,14]. To measure the intensity of TMRE signal, mitochondria in the fluorescent images were segmented using Fiji image software to generate a binary mask (S4 Fig).…”

Section: Depletion Of Escrt Components Does Not Rescue the Fragmentedmentioning

confidence: 99%

“…We propose that the induction of autophagy partially restores membrane potential and thereby suppresses fzo-1(tm1133)-induced UPR mt . Interestingly, a decrease in mitochondrial membrane potential has recently been shown to be the signal for UPR mt induction [10]. Therefore, some aspect of mitochondrial stress that leads to both decreased membrane potential and the…”

Section: Induction Of Autophagy Increases Mitochondrial Membrane Potementioning

confidence: 99%

“…The consequences with respect to mitochondrial function and cellular homeostasis of disrupting mitochondrial dynamics are not yet fully understood; however, it has recently been demonstrated that this activates a retrograde quality control signaling pathway referred to as the 'mitochondrial Unfolded Protein Response' (UPR mt ) [7,8]. In C. elegans, UPR mt is activated upon mitochondrial stress, which leads to a decrease in mitochondrial membrane potential and the subsequent import into the nucleus of the 'Activating Transcription Factor associated with Stress 1' (ATFS-1 ATF4,5 ) [9,10]. ATFS-1 ATF4,5 harbors both an N-terminal mitochondrial targeting sequence and a C-terminal nuclear localization sequence and is normally imported into mitochondria [11].…”

Section: Introductionmentioning

confidence: 99%

“…ATFS-1 ATF4,5 harbors both an N-terminal mitochondrial targeting sequence and a C-terminal nuclear localization sequence and is normally imported into mitochondria [11]. Upon mitochondrial stress, ATFS-1 ATF4,5 is imported into the nucleus, where it cooperates with the proteins UBL-5 UBL5 and DVE-1 SATB1 to promote the transcription of genes that act to restore mitochondrial function and to adjust cellular metabolism [9,10,12,13]. Among these genes are the mitochondrial chaperone genes hsp-6 mtHSP70 and hsp-60 HSP60 , the transcriptional upregulation of which is commonly used to monitor UPR mt activation [14].…”

Section: Introductionmentioning

confidence: 99%

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Autophagy compensates for defects in mitochondrial dynamics

et al. 2020

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Compromising mitochondrial fusion or fission disrupts cellular homeostasis; however, the underlying mechanism(s) are not fully understood. The loss of C. elegans fzo-1 MFN results in mitochondrial fragmentation, decreased mitochondrial membrane potential and the induction of the mitochondrial unfolded protein response (UPR mt). We performed a genome-wide RNAi screen for genes that when knocked-down suppress fzo-1 MFN (lf)-induced UPR mt. Of the 299 genes identified, 143 encode negative regulators of autophagy, many of which have previously not been implicated in this cellular quality control mechanism. We present evidence that increased autophagic flux suppresses fzo-1 MFN (lf)-induced UPR mt by increasing mitochondrial membrane potential rather than restoring mitochondrial morphology. Furthermore, we demonstrate that increased autophagic flux also suppresses UPR mt induction in response to a block in mitochondrial fission, but not in response to the loss of spg-7 AFG3L2 , which encodes a mitochondrial metalloprotease. Finally, we found that blocking mitochondrial fusion or fission leads to increased levels of certain types of triacylglycerols and that this is at least partially reverted by the induction of autophagy. We propose that the breakdown of these triacylglycerols through autophagy leads to elevated metabolic activity, thereby increasing mitochondrial membrane potential and restoring mitochondrial and cellular homeostasis.

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Section: Resultsmentioning

confidence: 99%

Section: Depletion Of Escrt Components Does Not Rescue the Fragmentedmentioning

confidence: 99%

Section: Induction Of Autophagy Increases Mitochondrial Membrane Potementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Autophagy compensates for defects in mitochondrial dynamics

et al. 2020

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Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond

2023

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Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import. K E Y W O R D Smetabolism, mitochondrial protein import, mitochondrial unfolded protein response, mitophagy, proteostasis Recent findings from system biology studies in whole cells (in vivo) have highlighted the mitochondrial protein import system as a critical

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Methods to Study the Mitochondrial Unfolded Protein Response (UPRmt) in Caenorhabditis elegans

Haeussler

Conradt

2022

Methods in Molecular Biology

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The nematode Caenorhabditis elegans is a powerful model to study cellular stress responses.Due to its transparency and ease of genetic manipulation, C. elegans is especially suitable for fluorescence microscopy. As a result, studies of C. elegans using different fluorescent reporters have led to the discovery of key players of cellular stress response pathways, including the mitochondrial unfolded protein response (UPR mt ). UPR mt is a protective retrograde signaling pathway that ensures mitochondrial homeostasis. The nuclear genes hsp-6 and hsp-60 encode mitochondrial chaperones and are highly expressed upon UPR mt induction. The transcriptional reporters of these genes, hsp-6::gfp and hsp-60::gfp, have been instrumental for monitoring this pathway in live animals. Additional tools for studying UPR mt include fusion proteins of ATFS-1 and DVE-1, ATFS-1::GFP and DVE-1::GFP, key players of the UPR mt pathway. In this protocol, we discuss advantages and limitations of currently available methods and reporters, and we provide detailed instructions on how to image and quantify reporter expression.

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Compromised Mitochondrial Protein Import Acts as a Signal for UPRmt

Cited by 131 publications

References 53 publications

Autophagy compensates for defects in mitochondrial dynamics

Autophagy compensates for defects in mitochondrial dynamics

Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond

Methods to Study the Mitochondrial Unfolded Protein Response (UPRmt) in Caenorhabditis elegans

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