Stress Responses Elicited by Misfolded Proteins Targeted to Mitochondria

Rao, Kannan Boosi Narayana; Pandey, Pallavi; Sarkar, Rajasri; Ghosh, Asmita; Mansuri, Shemin; Ali, Khadem; Majumder, Priyanka; Kumar, K. Ranjith; A, Ray; Raychaudhuri, Santwana; Mapa, Koyeli

doi:10.1016/j.jmb.2022.167618

Cited by 8 publications

(10 citation statements)

References 42 publications

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“…The ISR mt can occur as a result of protein misfolding in mitochondria ( Narayana Rao et al, 2022 ). It induces activating transcription factor (ATF)4 and ATF5, which downregulate the transcription of many genes, while upregulating the expression of genes involved in proteostasis.…”

Section: Introductionmentioning

confidence: 99%

Comparative multi-omic analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Sayles,

Napierala,

Anrather

et al. 2023

Disease Models &Amp; Mechanisms

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Cardiomyopathy is often fatal in Friedreich ataxia (FA). However, FA hearts maintain adequate function until advanced disease stages, suggesting initial adaptation to the loss of frataxin (FXN). Conditional cardiac knockout mouse models of FXN show transcriptional and metabolic profiles of the mitochondrial integrated stress response (ISRmt), which could play an adaptive role. However, the ISRmt has not been investigated in models with disease-relevant, partial decrease in FXN. We characterized the heart transcriptomes and metabolomes of three mouse models with varying degrees of FXN depletion: YG8-800, KIKO-700 and FXNG127V. Few metabolites were changed in YG8-800 mice, which did not provide a signature of cardiomyopathy or ISRmt; several metabolites were altered in FXNG127V and KIKO-700 hearts. Transcriptional changes were found in all models, but differentially expressed genes consistent with cardiomyopathy and ISRmt were only identified in FXNG127V hearts. However, these changes were surprisingly mild even at advanced age (18 months), despite a severe decrease in FXN levels to 1% of those of wild type. These findings indicate that the mouse heart has low reliance on FXN, highlighting the difficulty in modeling genetically relevant FA cardiomyopathy.

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Section: Introductionmentioning

confidence: 99%

Comparative multi-omic analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Sayles,

Napierala,

Anrather

et al. 2023

Disease Models &Amp; Mechanisms

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“…Although no previous issues have been reported with TEVp expression in yeast ( 22 , 23 , 41 ) and TEVp targeted to mitochondria has been utilized to process fumarase ( 42 ), we observe growth arrest when TEV is co-expressed and targeted to mitochondria with our polyproteins. Since Nif polypeptides are undetectable under these conditions, cleavage and release of misfolded proteins may result in proteotoxic stress ( 43 ). The endogenous MPP-based polyprotein strategy clearly bypasses the issues observed with the TEV-based system, potentially because each Nif component is cleaved and folded discretely as the polyprotein passes through the inner mitochondrial membrane.…”

Section: Discussionmentioning

confidence: 99%

Organelle-dependent polyprotein designs enable stoichiometric expression of nitrogen fixation components targeted to mitochondria

Yang

南保明日香

Liu

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Introducing nitrogen fixation ( nif ) genes into eukaryotic genomes and targeting Nif components to mitochondria or chloroplasts is a promising strategy for engineering nitrogen-fixing plants. A prerequisite for achieving nitrogen fixation in crops is stable and stoichiometric expression of each component in organelles. Previously, we designed a polyprotein-based nitrogenase system depending on Tobacco Etch Virus protease (TEVp) to release functional Nif components from five polyproteins. Although this system satisfies the demand for specific expression ratios of Nif components in Escherichia coli , we encountered issues with TEVp cleavage of polyproteins targeted to yeast mitochondria. To overcome this obstacle, a version of the Nif polyprotein system was constructed by replacing TEVp cleavage sites with minimal peptide sequences, identified by knowledge-based engineering, that are susceptible to cleavage by the endogenous mitochondrial-processing peptidase. This replacement not only further reduces the number of genes required, but also prevents potential precleavage of polyproteins outside the target organelle. This version of the polyprotein-based nitrogenase system achieved levels of nitrogenase activity in E. coli , comparable to those observed with the TEVp-based polyprotein nitrogenase system. When applied to yeast mitochondria, stable and balanced expression of Nif components was realized. This strategy has potential advantages, not only for transferring nitrogen fixation to eukaryotic cells, but also for the engineering of other metabolic pathways that require mitochondrial compartmentalization.

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“…F. Similar to panel E, growth assay by serial drop dilutions was performed for the WT, sse1Δ and all other single deletion strains for CLIPS proteins apart from Sse1, (ssb1Δ, ssz1Δ, zuo1Δ, jjj1Δ, snl1Δ, gim2Δ, gim3Δ, gim5Δ, cpr6Δ, cct8Δ, and egd1Δ) in YPAD plates in permissive temperature (30°C) (left panel), heat shock condition (37°C) (middle panel) and in presence of an optimal concentration of tunicamycin (2.5 µg/ml) (right panel). A-C. Transcriptome analysis of WT and sse1Δ strains in untreated condition and after treatment with tunicamycin (2.5 μg/ml) along with other yeast strains of same genetic background as described previously [24] was done by RNA sequencing. The outputs were converted to Z scores.…”

Section: Discussionmentioning

confidence: 99%

“…For transcriptome analysis, along with 40 other yeast samples of similar genetic background, WT and sse1Δ strains were subjected to RNA sequencing in untreated and Tm-treated conditions. To identify the genes that are differentially upregulated or downregulated at a particular sample, the Z-score of expression for each gene across all these yeast strains was calculated as described previously [24]. The genes above or below Z-score 2 at a particular condition were considered as significantly upregulated or downregulated, respectively.…”

Section: Cellular Response To Tm-induced Er Stress Is Distinctly Diff...mentioning

confidence: 99%

Sse1, Hsp110 chaperone of yeast, controls the cellular fate during Endoplasmic Reticulum-stress

Jha

Kumar

Sharma

et al. 2023

Preprint

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Sse1 is a cytosolic Hsp110 molecular chaperone of yeast, Saccharomyces cerevisiae. Its multifaceted roles in cellular protein homeostasis as Nucleotide Exchange Factor (NEF), as protein-disaggregase and as a Chaperone linked to Protein Synthesis (CLIPS), are well documented. In the currently study, we show that SSE1 genetically interacts with IRE1 and HAC1, the Endoplasmic Reticulum-Unfolded Protein Response (ER-UPR) sensors implicating its role in ER protein homeostasis. Interestingly, absence of this chaperone imparts unusual resistance to tunicamycin-induced ER stress which depends on the intact Ire1-Hac1 mediated ER-UPR signalling. Furthermore, cells lacking SSE1 show ER-stress-responsive inefficient reorganization of translating ribosomes from polysomes to monosomes and increased monosome content that drive uninterrupted protein translation. In consequence, the kinetics of ER-UPR is starkly different in sse1Δ strain where we show that stress response induction and restoration of homeostasis is prominently faster in contrast to the wildtype (WT) cells. Importantly, Sse1 plays a critical role in controlling the ER-stress mediated cell division arrest which is escaped in sse1Δ strain during chronic tunicamycin stress. Consequently, sse1Δ strain shows significantly higher cell viability in comparison to WT yeast, following short-term as well as long-term tunicamycin stress. In summary, we demonstrate a new role of Sse1 in ER protein homeostasis where the chaperone genetically interacts with ER-UPR pathway, controls the protein translation during ER stress and the kinetics of ER-UPR. More importantly, we show the crtiical role of Sse1 in regulating the ER-stress-induced cell division arrest and cell death during global ER stress by tunicamycin.

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Stress Responses Elicited by Misfolded Proteins Targeted to Mitochondria

Cited by 8 publications

References 42 publications

Comparative multi-omic analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Comparative multi-omic analyses of cardiac mitochondrial stress in three mouse models of frataxin deficiency

Organelle-dependent polyprotein designs enable stoichiometric expression of nitrogen fixation components targeted to mitochondria

Sse1, Hsp110 chaperone of yeast, controls the cellular fate during Endoplasmic Reticulum-stress

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