scholarly journals Mitochondrial Metabolic Signatures in Hepatocellular Carcinoma

Cells ◽  
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.

scholarly journals Role of the mitochondrial stress response in human cancer progression

2020 ◽  
Vol 245 (10) ◽  
pp. 861-878 ◽  
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.

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

2014 ◽  
Vol 462 (2) ◽  
pp. 359-371 ◽  
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.

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

2020 ◽  
Author(s):  
Terytty Yang Li ◽  
Maroun Bou Sleiman ◽  
Hao Li ◽  
Arwen W. Gao ◽  
Adrienne Mottis ◽  
...  
Keyword(s):  
Stress Response ◽  
Stress Responses ◽  
Mammalian Cells ◽  
Amyloid Β ◽  
Human Populations ◽  
Histone Demethylases ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
Evolutionarily Conserved ◽  
Protein Response

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.

scholarly journals Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity

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.

scholarly journals Mitochondrial Stress Signaling Promotes Cellular Adaptations

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Jayne Alexandra Barbour ◽  
Nigel Turner
Keyword(s):  
Mitochondrial Dysfunction ◽  
Morphological Changes ◽  
Stress Signaling ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
Stressful Environment ◽  
Repair Enzymes ◽  
Successful Induction ◽  
Protein Response ◽  
Over Time

Mitochondrial dysfunction has been implicated in the aetiology of many complex diseases, as well as the ageing process. Much of the research on mitochondrial dysfunction has focused on how mitochondrial damage may potentiate pathological phenotypes. The purpose of this review is to draw attention to the less well-studied mechanisms by which the cell adapts to mitochondrial perturbations. This involves communication of stress to the cell and successful induction of quality control responses, which include mitophagy, unfolded protein response, upregulation of antioxidant and DNA repair enzymes, morphological changes, and if all else fails apoptosis. The mitochondrion is an inherently stressful environment and we speculate that dysregulation of stress signaling or an inability to switch on these adaptations during times of mitochondrial stress may underpin mitochondrial dysfunction and hence amount to pathological states over time.

scholarly journals Proteasome activity contributes to pro-survival response upon mild mitochondrial stress in Caenorhabditis elegans

PLoS Biology ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. e3001302
Author(s):  
Maria Sladowska ◽  
Michał Turek ◽  
Min-Ji Kim ◽  
Krzysztof Drabikowski ◽  
Ben Hur Marins Mussulini ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Life Span ◽  
Mitochondrial Dysfunction ◽  
Unfolded Protein Response ◽  
Mitochondrial Protein ◽  
Yeast Cells ◽  
Mitochondrial Proteins ◽  
Mitochondrial Stress ◽  
Unfolded Protein ◽  
Protein Response

Defects in mitochondrial function activate compensatory responses in the cell. Mitochondrial stress that is caused by unfolded proteins inside the organelle induces a transcriptional response (termed the “mitochondrial unfolded protein response” [UPRmt]) that is mediated by activating transcription factor associated with stress 1 (ATFS-1). The UPRmt increases mitochondrial protein quality control. Mitochondrial dysfunction frequently causes defects in the import of proteins, resulting in the accumulation of mitochondrial proteins outside the organelle. In yeast, cells respond to mistargeted mitochondrial proteins by increasing activity of the proteasome in the cytosol (termed the “unfolded protein response activated by mistargeting of proteins” [UPRam]). The presence and relevance of this response in higher eukaryotes is unclear. Here, we demonstrate that defects in mitochondrial protein import in Caenorhabditis elegans lead to proteasome activation and life span extension. Both proteasome activation and life span prolongation partially depend on ATFS-1, despite its lack of influence on proteasomal gene transcription. Importantly, life span prolongation depends on the fully assembled proteasome. Our data provide a link between mitochondrial dysfunction and proteasomal activity and demonstrate its direct relevance to mechanisms that promote longevity.

Unfolded protein response activation contributes to chemoresistance in hepatocellular carcinoma

2010 ◽  
Vol 22 (9) ◽  
pp. 1099-1105 ◽  
Author(s):  
Feras Y. Al-Rawashdeh ◽  
Peter Scriven ◽  
Ian C. Cameron ◽  
Patricia V. Vergani ◽  
Lynda Wyld
Keyword(s):  
Hepatocellular Carcinoma ◽  
Unfolded Protein Response ◽  
Unfolded Protein ◽  
Protein Response ◽  
Response Activation

scholarly journals Herpesviruses and the Unfolded Protein Response

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 17 ◽  
Author(s):  
Benjamin P. Johnston ◽  
Craig McCormick
Keyword(s):  
Unfolded Protein Response ◽  
Stress Responses ◽  
Immune Surveillance ◽  
Lytic Replication ◽  
Glycoprotein Synthesis ◽  
Unfolded Protein ◽  
Transcriptional Reprogramming ◽  
Molecular Events ◽  
The Unfolded Protein Response ◽  
Protein Response

Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from “helper” to “executioner”, triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection.

scholarly journals The Role of the ER-Induced UPR Pathway and the Efficacy of Its Inhibitors and Inducers in the Inhibition of Tumor Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Anna Walczak ◽  
Kinga Gradzik ◽  
Jacek Kabzinski ◽  
Karolina Przybylowska-Sygut ◽  
Ireneusz Majsterek
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Unfolded Proteins ◽  
Cell Protection ◽  
Protection Mechanism ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
A Cell ◽  
The Unfolded Protein Response ◽  
Protein Response

Cancer is the second most frequent cause of death worldwide. It is considered to be one of the most dangerous diseases, and there is still no effective treatment for many types of cancer. Since cancerous cells have a high proliferation rate, it is pivotal for their proper functioning to have the well-functioning protein machinery. Correct protein processing and folding are crucial to maintain tumor homeostasis. Endoplasmic reticulum (ER) stress is one of the leading factors that cause disturbances in these processes. It is induced by impaired function of the ER and accumulation of unfolded proteins. Induction of ER stress affects many molecular pathways that cause the unfolded protein response (UPR). This is the way in which cells can adapt to the new conditions, but when ER stress cannot be resolved, the UPR induces cell death. The molecular mechanisms of this double-edged sword process are involved in the transition of the UPR either in a cell protection mechanism or in apoptosis. However, this process remains poorly understood but seems to be crucial in the treatment of many diseases that are related to ER stress. Hence, understanding the ER stress response, especially in the aspect of pathological consequences of UPR, has the potential to allow us to develop novel therapies and new diagnostic and prognostic markers for cancer.

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