A conserved role of CBP/p300 in mitochondrial stress response and longevity

Abstract Organisms respond to mitochondrial stress by activating multiple defense pathways including the mitochondrial unfolded protein response (UPRmt). However, how different layers of UPRmt regulators are orchestrated to transcriptionally activate the stress responses remains largely unknown. Here we identified CBP-1, the worm ortholog of the mammalian acetyltransferases CBP/p300, as an essential regulator for UPRmt activation, as well as for mitochondrial stress-induced immune response, reduction of amyloid-β aggregation and lifespan extension in Caenorhabditis elegans. Mechanistically, CBP-1 acts downstream of histone demethylases, JMJD-1.2/JMJD-3.1, and upstream of UPRmt transcription factors including ATFS-1, to systematically induce a broad spectrum of UPRmt genes and execute multiple beneficial functions. In mouse and human populations, transcript levels of CBP/p300 positively correlate with UPRmt transcripts and longevity. Furthermore, CBP/p300 inhibition disrupts, while forced expression of p300 is sufficient to activate, the UPRmt in mammalian cells. These results highlight an evolutionarily conserved mechanism that determines mitochondrial stress response, and promotes health and longevity through CBP/p300.

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Role of the mitochondrial stress response in human cancer progression

Experimental Biology and Medicine ◽

10.1177/1535370220920558 ◽

2020 ◽

Vol 245 (10) ◽

pp. 861-878 ◽

Cited By ~ 3

Author(s):

Sheng-Fan Wang ◽

Shiuan Chen ◽

Ling-Ming Tseng ◽

Hsin-Chen Lee

Keyword(s):

Stress Response ◽

Mitochondrial Dysfunction ◽

Cancer Progression ◽

Stress Responses ◽

Retrograde Signaling ◽

Cancer Targeting ◽

Mitochondrial Stress ◽

Unfolded Protein ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

Mitochondria are important organelles that are responsible for cellular energy metabolism, cellular redox/calcium homeostasis, and cell death regulation in mammalian cells. Mitochondrial dysfunction is involved in various diseases, such as neurodegenerative diseases, cardiovascular diseases, immune disorders, and cancer. Defective mitochondria and metabolism remodeling are common characteristics in cancer cells. Several factors, such as mitochondrial DNA copy number changes, mitochondrial DNA mutations, mitochondrial enzyme defects, and mitochondrial dynamic changes, may contribute to mitochondrial dysfunction in cancer cells. Some lines of evidence have shown that mitochondrial dysfunction may promote cancer progression. Here, several mitochondrial stress responses, including the mitochondrial unfolded protein response and the integrated stress response, and several mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and others) are reviewed; these pathways and molecules are considered to act as retrograde signaling regulators in the development and progression of cancer. Targeting these components of the mitochondrial stress response may be an important strategy for cancer treatment. Impact statement Dysregulated mitochondria often occurred in cancers. Mitochondrial dysfunction might contribute to cancer progression. We reviewed several mitochondrial stresses in cancers. Mitochondrial stress responses might contribute to cancer progression. Several mitochondrion-derived molecules (ROS, Ca2+, oncometabolites, exported mtDNA, mitochondrial double-stranded RNA, humanin, and MOTS-c), integrated stress response, and mitochondrial unfolded protein response act as retrograde signaling pathways and might be critical in the development and progression of cancer. Targeting these mitochondrial stress responses may be an important strategy for cancer treatment.

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Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity

Nature Communications ◽

10.1038/s41467-020-18501-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Li-Wa Shao ◽

Qi Peng ◽

Mingyue Dong ◽

Kaiyu Gao ◽

Yumei Li ◽

...

Keyword(s):

Histone Deacetylase ◽

Mammalian Cells ◽

Metabolic Reprogramming ◽

Mitochondrial Stress ◽

C Elegans ◽

Unfolded Protein ◽

Mitochondrial Homeostasis ◽

Evolutionarily Conserved ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

Abstract The ability to detect, respond and adapt to mitochondrial stress ensures the development and survival of organisms. Caenorhabditis elegans responds to mitochondrial stress by activating the mitochondrial unfolded protein response (UPRmt) to buffer the mitochondrial folding environment, rewire the metabolic state, and promote innate immunity and lifespan extension. Here we show that HDA-1, the C. elegans ortholog of mammalian histone deacetylase (HDAC) is required for mitochondrial stress-mediated activation of UPRmt. HDA-1 interacts and coordinates with the genome organizer DVE-1 to induce the transcription of a broad spectrum of UPRmt, innate immune response and metabolic reprogramming genes. In rhesus monkey and human tissues, HDAC1/2 transcript levels correlate with the expression of UPRmt genes. Knocking down or pharmacological inhibition of HDAC1/2 disrupts the activation of the UPRmt and the mitochondrial network in mammalian cells. Our results underscore an evolutionarily conserved mechanism of HDAC1/2 in modulating mitochondrial homeostasis and regulating longevity.

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Homolog of ELAC2 is a central regulator of the mitochondrial unfolded protein response

10.1101/2021.06.22.449331 ◽

2021 ◽

Author(s):

James P Held ◽

Benjamin R Saunders ◽

Claudia V Pereria ◽

Maulik R Patel

Keyword(s):

Transcription Factors ◽

Stress Response ◽

Unfolded Protein Response ◽

Negative Regulation ◽

Mitochondrial Stress ◽

Trna Processing ◽

Unfolded Protein ◽

Necessary And Sufficient ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

The mitochondrial unfolded protein response (UPRmt) has emerged as a predominant mechanism that preserves mitochondrial function. Consequently, multiple pathways likely exist to modulate UPRmt. We unexpectedly discovered that the tRNA processing enzyme, homolog of ELAC2 (HOE-1), is central to UPRmt regulation in Caenorhabditis elegans. We find that nuclear HOE-1 is necessary and sufficient to robustly activate UPRmt. We show that HOE-1 acts via transcription factors ATFS-1 and DVE-1 that are crucial for UPRmt. Mechanistically, we show that HOE-1 likely mediates its effects via tRNAs, as blocking tRNA export prevents HOE-1-induced UPRmt. Interestingly, we find that HOE-1 does not act via the integrated stress response, which can be activated by uncharged tRNAs, pointing towards its reliance on a new mechanism. Finally, we show that the subcellular localization of HOE-1 is responsive to mitochondrial stress and is subject to negative regulation via ATFS-1. Together, we have discovered a novel RNA-based cellular pathway that modulates UPRmt.

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Multilevel regulation of endoplasmic reticulum stress responses in plants: where old roads and new paths meet

Journal of Experimental Botany ◽

10.1093/jxb/erz487 ◽

2019 ◽

Vol 71 (5) ◽

pp. 1659-1667 ◽

Cited By ~ 10

Author(s):

Taiaba Afrin ◽

Danish Diwan ◽

Katrina Sahawneh ◽

Karolina Pajerowska-Mukhtar

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Stress Responses ◽

Translational Control ◽

Protein Quality ◽

Unfolded Protein ◽

Transcriptional Gene Regulation ◽

The Unfolded Protein Response ◽

Protein Response

Abstract The sessile lifestyle of plants requires them to cope with a multitude of stresses in situ. In response to diverse environmental and intracellular cues, plant cells respond by massive reprogramming of transcription and translation of stress response regulators, many of which rely on endoplasmic reticulum (ER) processing. This increased protein synthesis could exceed the capacity of precise protein quality control, leading to the accumulation of unfolded and/or misfolded proteins that triggers the unfolded protein response (UPR). Such cellular stress responses are multilayered and executed in different cellular compartments. Here, we will discuss the three main branches of UPR signaling in diverse eukaryotic systems, and describe various levels of ER stress response regulation that encompass transcriptional gene regulation by master transcription factors, post-transcriptional activities including cytoplasmic splicing, translational control, and multiple post-translational events such as peptide modifications and cleavage. In addition, we will discuss the roles of plant ER stress sensors in abiotic and biotic stress responses and speculate on the future prospects of engineering these signaling events for heightened stress tolerance.

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Complex IV-deficient Surf1−/− mice initiate mitochondrial stress responses

Biochemical Journal ◽

10.1042/bj20140291 ◽

2014 ◽

Vol 462 (2) ◽

pp. 359-371 ◽

Cited By ~ 64

Author(s):

Daniel A. Pulliam ◽

Sathyaseelan S. Deepa ◽

Yuhong Liu ◽

Shauna Hill ◽

Ai-Ling Lin ◽

...

Keyword(s):

Mitochondrial Biogenesis ◽

Stress Responses ◽

Complex Iv ◽

Mitochondrial Stress ◽

Nrf2 Pathway ◽

Compensatory Responses ◽

Unfolded Protein ◽

Assembly Factor ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

Loss of complex IV assembly factor SURF1 in mice results in compensatory responses including mitochondrial biogenesis, the Nrf2 pathway and the mitochondrial unfolded protein response. These compensatory responses may contribute to the lack of deleterious phenotypes under basal conditions.

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FSHR-1/GPCR Regulates the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans

Genetics ◽

10.1534/genetics.119.302947 ◽

2019 ◽

Vol 214 (2) ◽

pp. 409-418 ◽

Cited By ~ 4

Author(s):

Sungjin Kim ◽

Derek Sieburth

Keyword(s):

Caenorhabditis Elegans ◽

Unfolded Protein Response ◽

Mitochondrial Stress ◽

Unfolded Protein ◽

Mitochondrial Homeostasis ◽

Link Type ◽

Link Functions ◽

Evolutionarily Conserved ◽

Protein Response ◽

Mitochondrial Unfolded Protein Response

The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In Caenorhabditis elegans, the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPRmt. The mechanisms by which mitochondrial stress is sensed by neurons and transmitted to distal tissues are not fully understood. Here, we identify a role for the conserved follicle-stimulating hormone G protein-coupled receptor, FSHR-1, in promoting UPRmt activation. Genetic deficiency of fshr-1 severely attenuates UPRmt activation and organism-wide survival in response to mitochondrial stress. FSHR-1 functions in a common genetic pathway with SPHK-1/sphingosine kinase to promote UPRmt activation, and FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine. Through tissue-specific rescue assays, we show that FSHR-1 functions in neurons to activate the UPRmt, to promote mitochondrial association of SPHK-1 in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that FSHR-1 functions cell nonautonomously in neurons to activate UPRmt upstream of SPHK-1 signaling in the intestine.

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Adaptation to mitochondrial stress requires CHOP-directed tuning of ISR

Science Advances ◽

10.1126/sciadv.abf0971 ◽

2021 ◽

Vol 7 (22) ◽

pp. eabf0971

Author(s):

Sophie Kaspar ◽

Christian Oertlin ◽

Karolina Szczepanowska ◽

Alexandra Kukat ◽

Katharina Senft ◽

...

Keyword(s):

Stress Response ◽

Mitochondrial Gene ◽

Transcriptional Response ◽

Premature Death ◽

Fine Tuning ◽

Mitochondrial Stress ◽

Respiratory Chain Deficiency ◽

Unfolded Protein ◽

Protein Response

In response to disturbed mitochondrial gene expression and protein synthesis, an adaptive transcriptional response sharing a signature of the integrated stress response (ISR) is activated. We report an intricate interplay between three transcription factors regulating the mitochondrial stress response: CHOP, C/EBPβ, and ATF4. We show that CHOP acts as a rheostat that attenuates prolonged ISR, prevents unfavorable metabolic alterations, and postpones the onset of mitochondrial cardiomyopathy. Upon mitochondrial dysfunction, CHOP interaction with C/EBPβ is needed to adjust ATF4 levels, thus preventing overactivation of the ATF4-regulated transcriptional program. Failure of this interaction switches ISR from an acute to a chronic state, leading to early respiratory chain deficiency, energy crisis, and premature death. Therefore, contrary to its previously proposed role as a transcriptional activator of mitochondrial unfolded protein response, our results highlight a role of CHOP in the fine-tuning of mitochondrial ISR in mammals.

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Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma

Cells ◽

10.3390/cells10081901 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1901

Author(s):

Ho-Yeop Lee ◽

Ha Thi Nga ◽

Jingwen Tian ◽

Hyon-Seung Yi

Keyword(s):

Hepatocellular Carcinoma ◽

Mitochondrial Dysfunction ◽

Stress Responses ◽

Metabolic Reprogramming ◽

Ros Production ◽

Unfolded Proteins ◽

Mitochondrial Stress ◽

Unfolded Protein ◽

Protein Response ◽

Metabolic Signatures

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. HCC progression and metastasis are closely related to altered mitochondrial metabolism, including mitochondrial stress responses, metabolic reprogramming, and mitoribosomal defects. Mitochondrial oxidative phosphorylation (OXPHOS) defects and reactive oxygen species (ROS) production are attributed to mitochondrial dysfunction. In response to oxidative stress caused by increased ROS production, misfolded or unfolded proteins can accumulate in the mitochondrial matrix, leading to initiation of the mitochondrial unfolded protein response (UPRmt). The mitokines FGF21 and GDF15 are upregulated during UPRmt and their levels are positively correlated with liver cancer development, progression, and metastasis. In addition, mitoribosome biogenesis is important for the regulation of mitochondrial respiration, cell viability, and differentiation. Mitoribosomal defects cause OXPHOS impairment, mitochondrial dysfunction, and increased production of ROS, which are associated with HCC progression in mouse models and human HCC patients. In this paper, we focus on the role of mitochondrial metabolic signatures in the development and progression of HCC. Furthermore, we provide a comprehensive review of cell autonomous and cell non-autonomous mitochondrial stress responses during HCC progression and metastasis.

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FSHR-1/GPCR activates the mitochondrial unfolded protein response in Caenorhabditis elegans

10.1101/586883 ◽

2019 ◽

Author(s):

Sungjin Kim ◽

Derek Sieburth

Keyword(s):

Unfolded Protein Response ◽

Mitochondrial Stress ◽

C Elegans ◽

Unfolded Protein ◽

Mitochondrial Homeostasis ◽

Evolutionarily Conserved ◽

Genetic Deficiency ◽

Protein Response ◽

G Protein Coupled ◽

Mitochondrial Unfolded Protein Response

AbstractThe mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive response that functions to maintain mitochondrial homeostasis following mitochondrial damage. In C. elegans, the nervous system plays a central role in responding to mitochondrial stress by releasing endocrine signals that act upon distal tissues to activate the UPRmt. The mechanisms by which mitochondrial stress is sensed by neurons and transmitted to distal tissues is not fully understood. Here, we identify a role for the conserved follicle-stimulating hormone G protein coupled receptor (GPCR), FSHR-1, in promoting UPRmt activation. Genetic deficiency of fshr-1 severely attenuates UPRmt activation and organism-wide survival in response to mitochondrial stress. FSHR-1 functions in a common genetic pathway with SPHK-1/sphingosine kinase to promote UPRmt activation, and FSHR-1 regulates the mitochondrial association of SPHK-1 in the intestine. Through tissue-specific rescue assays, we show that FSHR-1 functions in neurons to activate the UPRmt, to promote mitochondrial association of SPHK-1 in the intestine, and to promote organism-wide survival in response to mitochondrial stress. We propose that FSHR-1 functions cell non-autonomously in neurons to activate UPRmt upstream of SPHK-1 signaling in the intestine.

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Yeast FIT2 homolog is necessary to maintain cellular proteostasis by regulating lipid homeostasis

10.1101/2020.04.06.027847 ◽

2020 ◽

Author(s):

Peter Shyu ◽

Wei Sheng Yap ◽

Maria L. Gaspar ◽

Stephen A. Jesch ◽

Charlie Marvalim ◽

...

Keyword(s):

Stress Response ◽

Lipid Homeostasis ◽

Compensatory Mechanism ◽

Intracellular Lipids ◽

Cellular Processes ◽

Unfolded Protein ◽

Protein Ubiquitination ◽

Evolutionarily Conserved ◽

Protein Response

Lipid droplets (LDs) have long been regarded as inert cytoplasmic organelles with the primary function of housing excess intracellular lipids. More recently, LDs have been strongly implicated in conditions of lipid and protein dysregulation. The fat storage inducing transmembrane (FIT) family of proteins comprises of evolutionarily conserved endoplasmic reticulum (ER)-resident proteins that have been reported to induce LD formation. Here, we establish a model system to study the role of S. cerevisiae FIT homologues (ScFIT), SCS3 and YFT2, in proteostasis and stress response pathways. While LD biogenesis and basal ER stress-induced unfolded protein response (UPR) remain unaltered in ScFIT mutants, SCS3 was found to be essential for proper stress-induced UPR activation and for viability in the absence of the sole yeast UPR transducer IRE1. Devoid of a functional UPR, scs3 mutants exhibited accumulation of triacylglycerol within the ER along with aberrant LD morphology, suggesting a UPR-dependent compensatory mechanism for LD maturation. Additionally, SCS3 was necessary to maintain phospholipid homeostasis. Strikingly, the absence of the ScFIT proteins results in the downregulation of the closely-related Heat Shock Response (HSR) pathway. In line with this observation, global protein ubiquitination and the turnover of both ER and cytoplasmic misfolded proteins is impaired in ScFIT cells, while a screen for interacting partners of Scs3 identifies components of the proteostatic machinery as putative targets. Taken together, these suggest that ScFIT proteins may modulate proteostasis and stress response pathways with lipid metabolism at the interface between the two cellular processes.

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