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Journal of Experimental & Clinical... Feb 2022Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is...
BACKGROUND
Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC).
METHODS
Immunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. Xenograft tumor model was performed in BALB/c nude mice to analyze the role of Drp1 on ESCC progression.
RESULTS
We found that Drp1 high expression is correlated with poor overall survival of ESCC patients. Drp1 overexpression promotes cell proliferation and xenograft ESCC tumor growth by triggering autophagy. Furthermore, we demonstrated that Drp1 overexpression disturbs mitochondrial function and subsequent induces mitochondrial DNA (mtDNA) released into the cytosol thereby inducing cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA activates the cGAS-STING pathway and facilitates autophagy, which promotes ESCC cancer growth. Moreover, mtDNA digestion with DNase I and autophagy inhibition with chloroquine attenuates the cGAS-STING pathway activation and ESCC cancer growth.
CONCLUSIONS
Our finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.
Topics: Animals; Autophagy; Cell Line, Tumor; Cell Proliferation; DNA, Mitochondrial; Disease Progression; Dynamins; Female; Humans; Mice; Mice, Knockout; Mice, Nude; Nucleotidyltransferases
PubMed: 35209954
DOI: 10.1186/s13046-022-02262-z -
Journal of Biomedical Science Jul 2023Dysregulating cellular metabolism is one of the emerging cancer hallmarks. Mitochondria are essential organelles responsible for numerous physiologic processes, such as... (Review)
Review
Dysregulating cellular metabolism is one of the emerging cancer hallmarks. Mitochondria are essential organelles responsible for numerous physiologic processes, such as energy production, cellular metabolism, apoptosis, and calcium and redox homeostasis. Although the "Warburg effect," in which cancer cells prefer aerobic glycolysis even under normal oxygen circumstances, was proposed a century ago, how mitochondrial dysfunction contributes to cancer progression is still unclear. This review discusses recent progress in the alterations of mitochondrial DNA (mtDNA) and mitochondrial dynamics in cancer malignant progression. Moreover, we integrate the possible regulatory mechanism of mitochondrial dysfunction-mediated mitochondrial retrograde signaling pathways, including mitochondrion-derived molecules (reactive oxygen species, calcium, oncometabolites, and mtDNA) and mitochondrial stress response pathways (mitochondrial unfolded protein response and integrated stress response) in cancer progression and provide the possible therapeutic targets. Furthermore, we discuss recent findings on the role of mitochondria in the immune regulatory function of immune cells and reveal the impact of the tumor microenvironment and metabolism remodeling on cancer immunity. Targeting the mitochondria and metabolism might improve cancer immunotherapy. These findings suggest that targeting mitochondrial retrograde signaling in cancer malignancy and modulating metabolism and mitochondria in cancer immunity might be promising treatment strategies for cancer patients and provide precise and personalized medicine against cancer.
Topics: Humans; Calcium; Neoplasms; Mitochondria; DNA, Mitochondrial; Reactive Oxygen Species; Tumor Microenvironment
PubMed: 37525297
DOI: 10.1186/s12929-023-00956-w -
Biochimica Et Biophysica Acta Feb 1999Mitochondria play a central role in cellular energy provision. The organelles contain their own genome with a modified genetic code. The mammalian mitochondrial genome... (Review)
Review
Mitochondria play a central role in cellular energy provision. The organelles contain their own genome with a modified genetic code. The mammalian mitochondrial genome is transmitted exclusively through the female germ line. The human mitochondrial DNA (mtDNA) is a double-stranded, circular molecule of 16569 bp and contains 37 genes coding for two rRNAs, 22 tRNAs and 13 polypeptides. The mtDNA-encoded polypeptides are all subunits of enzyme complexes of the oxidative phosphorylation system. Mitochondria are not self-supporting entities but rely heavily for their functions on imported nuclear gene products. The basic mechanisms of mitochondrial gene expression have been solved. Cis-acting mtDNA sequences have been characterised by sequence comparisons, mapping studies and mutation analysis both in vitro and in patients harbouring mtDNA mutations. Characterisation of trans-acting factors has proven more difficult but several key enzymes involved in mtDNA replication, transcription and protein synthesis have now been biochemically identified and some have been cloned. These studies revealed that, although some factors may have an additional function elsewhere in the cell, most are unique to mitochondria. It is expected that cell cultures of patients with mitochondrial diseases will increasingly be used to address fundamental questions about mtDNA expression.
Topics: Cells, Cultured; DNA Replication; DNA, Mitochondrial; Humans; Molecular Structure; Protein Biosynthesis; Transcription, Genetic
PubMed: 10076021
DOI: 10.1016/s0005-2728(98)00161-3 -
Physiology (Bethesda, Md.) Jul 2022Circulating cell-free mitochondrial DNA (ccf-mtDNA) released upon cell injury or death stimulates diverse pattern recognition receptors to activate innate immune... (Review)
Review
Circulating cell-free mitochondrial DNA (ccf-mtDNA) released upon cell injury or death stimulates diverse pattern recognition receptors to activate innate immune responses and initiate systemic inflammation. In this review, we discuss the temporal changes of ccf-mtDNA during pregnancy and its potential contribution to adverse pregnancy outcomes in pregnancy complications.
Topics: Cell-Free Nucleic Acids; DNA, Mitochondrial; Female; Humans; Inflammation; Mitochondria; Pregnancy
PubMed: 35001655
DOI: 10.1152/physiol.00037.2021 -
Molecular Oncology Sep 2022Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70.... (Review)
Review
Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70. The pathologies of both ageing and cancer have been characterized by respective groups of molecular hallmarks, and while some features are divergent between the two pathologies, several are shared. Perturbed mitochondrial function is one such common hallmark, and this observation therefore suggests that mitochondrial alterations may be of significance in age-related cancer development. There is now considerable evidence documenting the accumulation of somatic mitochondrial DNA (mtDNA) mutations in ageing human postmitotic and replicative tissues. Similarly, mutations of the mitochondrial genome have been reported in human cancers for decades. The plethora of functions in which mitochondria partake, such as oxidative phosphorylation, redox balance, apoptosis and numerous biosynthetic pathways, manifests a variety of ways in which alterations in mtDNA may contribute to tumour growth. However, the specific mechanisms by which mtDNA mutations contribute to tumour progression remain elusive and often contradictory. This review aims to consolidate current knowledge and describe future direction within the field.
Topics: Aging; DNA, Mitochondrial; Humans; Mitochondria; Mutation; Neoplasms
PubMed: 35842901
DOI: 10.1002/1878-0261.13291 -
Frontiers in Bioscience (Landmark... Mar 2017Mitochondria, are the powerhouses of cells, have their own DNA (mtDNA), regulate the transport of metabolites and ions, and impact cell physiology, survival, and death.... (Review)
Review
Mitochondria, are the powerhouses of cells, have their own DNA (mtDNA), regulate the transport of metabolites and ions, and impact cell physiology, survival, and death. Mitochondrial dysfunction, including impaired oxidative phosphorylation, preferentially affects heart function due to an imbalance of energy supply and demand. Recently, mitochondrial mutations and associated mitochondrial dysfunction were suggested as a causal factor of cardiac manifestations. Oxidative stress largely influences mtDNA stability due to oxidative modifications of mtDNA. Furthermore, the continuous replicative state of mtDNA and presence of minimal nucleoid structure render mitochondria vulnerable to oxidative damage and subsequent mutations, which impair mitochondrial functions. However, the occurrence of mtDNA heteroplasmy in the same mitochondrion or cell and presence of nuclear DNA-encoded mtDNA repair systems raise questions regarding whether oxidative stress-mediated mtDNA mutations are the major driving force in accumulation of mtDNA mutations. Here, we address the possible causes of mitochondrial DNA mutations and their involvement in cardiac manifestations. Current strategies for treatment related to mitochondrial mutations and/or dysfunction in cardiac manifestations are briefly discussed.
Topics: Animals; DNA Damage; DNA Repair; DNA, Mitochondrial; Heart Diseases; Humans; Mitochondria, Heart; Mitochondrial Diseases; Mutation; Oxidative Stress
PubMed: 28199200
DOI: 10.2741/4541 -
Experimental Gerontology Jul 2023Mitochondrial DNA (mtDNA) is as a double-stranded molecule existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous... (Review)
Review
Mitochondrial DNA (mtDNA) is as a double-stranded molecule existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous and/or environmental stressors. The coordination of mtDNA replication and transcription regulates the pace of mitochondrial biogenesis to guarantee the minimum number of organelles per cell. mtDNA inheritance follows a maternal lineage, although bi-parental inheritance has been reported in some species and in the case of mitochondrial diseases in humans. mtDNA mutations (e.g., point mutations, deletions, copy number variations) have been identified in the setting of several human diseases. For instance, sporadic and inherited rare disorders involving the nervous system as well higher risk of developing cancer and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, have been associated with polymorphic mtDNA variants. An accrual of mtDNA mutations has also been identified in several tissues and organs, including heart and muscle, of old experimental animals and humans, which may contribute to the development of aging phenotypes. The role played by mtDNA homeostasis and mtDNA quality control pathways in human health is actively investigated for the possibility of developing targeted therapeutics for a wide range of conditions.
Topics: Animals; Humans; DNA Copy Number Variations; DNA, Mitochondrial; Mutation; Aging; Neoplasms
PubMed: 37172915
DOI: 10.1016/j.exger.2023.112203 -
Mitochondrial DNA replication and repair defects: Clinical phenotypes and therapeutic interventions.Biochimica Et Biophysica Acta.... Jun 2022Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle... (Review)
Review
Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle contains its circular genome - mtDNA (mitochondrial DNA), that undergoes continuous cycles of replication and repair to maintain the mitochondrial genome integrity. The majority of the mitochondrial genes, including mitochondrial replisome and repair genes, are nuclear-encoded. Although the repair machinery of mitochondria is quite efficient, the mitochondrial genome is highly susceptible to oxidative damage and other types of exogenous and endogenous agent-induced DNA damage, due to the absence of protective histones and their proximity to the main ROS production sites. Mutations in replication and repair genes of mitochondria can result in mtDNA depletion and deletions subsequently leading to mitochondrial genome instability. The combined action of mutations and deletions can result in compromised mitochondrial genome maintenance and lead to various mitochondrial disorders. Here, we review the mechanism of mitochondrial DNA replication and repair process, key proteins involved, and their altered function in mitochondrial disorders. The focus of this review will be on the key genes of mitochondrial DNA replication and repair machinery and the clinical phenotypes associated with mutations in these genes.
Topics: DNA Replication; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Phenotype
PubMed: 35341749
DOI: 10.1016/j.bbabio.2022.148554 -
International Journal of Molecular... Sep 2022Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that... (Review)
Review
Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that can exist in multiple copies within the organelle. Both strands are translated and encode for 22 tRNAs, 2 rRNAs, and 13 proteins. mtDNA molecules are anchored to the inner mitochondrial membrane and, in association with proteins, form a structure called nucleoid, which exerts a structural and protective function. Indeed, mitochondria have evolved mechanisms necessary to protect their DNA from chemical and physical lesions such as DNA repair pathways similar to those present in the nucleus. However, there are mitochondria-specific mechanisms such as rapid mtDNA turnover, fission, fusion, and mitophagy. Nevertheless, mtDNA mutations may be abundant in somatic tissue due mainly to the proximity of the mtDNA to the oxidative phosphorylation (OXPHOS) system and, consequently, to the reactive oxygen species (ROS) formed during ATP production. In this review, we summarise the most common types of mtDNA lesions and mitochondria repair mechanisms. The second part of the review focuses on the physiological role of mtDNA damage in ageing and the effect of mtDNA mutations in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Considering the central role of mitochondria in maintaining cellular homeostasis, the analysis of mitochondrial function is a central point for developing personalised medicine.
Topics: Adenosine Triphosphate; DNA Damage; DNA Repair; DNA, Mitochondrial; Humans; Mitochondrial Diseases; Neurodegenerative Diseases; Reactive Oxygen Species
PubMed: 36232693
DOI: 10.3390/ijms231911391 -
Biochimica Et Biophysica Acta Nov 2015Mitochondrial DNA has long been posited as a likely target of oxidative damage induced mutation during the ageing process. Research over the past decades has uncovered... (Review)
Review
Mitochondrial DNA has long been posited as a likely target of oxidative damage induced mutation during the ageing process. Research over the past decades has uncovered the accumulation of mitochondrial DNA mutations in association with a mosaic pattern of cells displaying mitochondrial dysfunction in ageing individuals. Unfortunately, the underlying mechanisms are far less straightforward than originally anticipated. Recent research on mitochondria reveals that these genomes are far less helpless than originally envisioned. Additionally, new technologies have allowed us to analyze the mutational signatures of many more somatic mitochondrial DNA mutations, revealing surprising patterns that are inconsistent with a DNA-oxidative damage based hypothesis. In this review, we will discuss these recent observations and new insights into the eccentricities of mitochondrial genetics, and their impact on our understanding of mitochondrial mutations and their role in the ageing process. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Topics: Animals; DNA Damage; DNA Replication; DNA, Mitochondrial; Free Radicals; Humans; Mutation
PubMed: 26050972
DOI: 10.1016/j.bbabio.2015.06.001