Pub Date : 2024-12-13DOI: 10.1016/j.mito.2024.101999
Nandita Sharma , Kiran Heer , Saumya Raychaudhuri
VopE, a type III effector protein of Vibrio cholerae, modulates host mitochondrial function. Mitochondrial entry of VopE is directly linked with an N-terminal precursor sequence known as the mitochondrial targeting sequence or MTS. MTS of VopE is constituted with 23 amino acids. Earlier studies have shown the importance of leucine residue at position 4 in VopE translocation to mitochondria. In the present study, we have identified another leucine residue at position 15 contributing to the mitochondrial uptake of VopE in the yeast model system. Substitution of leucine15 with glutamate decreases mitochondrial localization and toxicity of the mutants.
{"title":"Substitution of leucine by glutamate perturbs VopE localization to mitochondria: Lessons from yeast model system","authors":"Nandita Sharma , Kiran Heer , Saumya Raychaudhuri","doi":"10.1016/j.mito.2024.101999","DOIUrl":"10.1016/j.mito.2024.101999","url":null,"abstract":"<div><div>VopE, a type III effector protein of <em>Vibrio cholerae</em>, modulates host mitochondrial function. Mitochondrial entry of VopE is directly linked with an N-terminal precursor sequence known as the mitochondrial targeting sequence or MTS. MTS of VopE is constituted with 23 amino acids. Earlier studies have shown the importance of leucine residue at position 4 in VopE translocation to mitochondria. In the present study, we have identified another leucine residue at position 15 contributing to the mitochondrial uptake of VopE in the yeast model system. Substitution of leucine<sup>15</sup> with glutamate decreases mitochondrial localization and toxicity of the mutants.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"81 ","pages":"Article 101999"},"PeriodicalIF":3.9,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142829441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09DOI: 10.1016/j.mito.2024.102000
Nishad Keethedeth, Rajesh Anantha Shenoi
Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.
{"title":"Mitochondria-targeted nanotherapeutics: A new frontier in neurodegenerative disease treatment","authors":"Nishad Keethedeth, Rajesh Anantha Shenoi","doi":"10.1016/j.mito.2024.102000","DOIUrl":"10.1016/j.mito.2024.102000","url":null,"abstract":"<div><div>Mitochondria are the seat of cellular energy and play key roles in regulating several cellular processes such as oxidative phosphorylation, respiration, calcium homeostasis and apoptotic pathways. Mitochondrial dysfunction results in error in oxidative phosphorylation, redox imbalance, mitochondrial DNA mutations, and disturbances in mitochondrial dynamics, all of which can lead to several metabolic and degenerative diseases. A plethora of studies have provided evidence for the involvement of mitochondrial dysfunction in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Hence mitochondria have been used as possible therapeutic targets in the regulation of neurodegenerative diseases. However, the double membranous structure of mitochondria poses an additional barrier to most drugs even if they are able to cross the plasma membrane. Most of the drugs acting on mitochondria also required very high doses to exhibit the desired mitochondrial accumulation and therapeutic effect which in-turn result in toxic effects. Mitochondrial targeting has been improved by direct conjugation of drugs to mitochondriotropic molecules like dequalinium (DQA) and triphenyl phosphonium (TPP) cations. But being cationic in nature, these molecules also exhibit toxicity at higher doses. In order to further improve the mitochondrial localization with minimal toxicity, TPP was conjugated with various nanomaterials like liposomes. inorganic nanoparticles, polymeric nanoparticles, micelles and dendrimers. This review provides an overview of the role of mitochondrial dysfunction in neurodegenerative diseases and various nanotherapeutic strategies for efficient targeting of mitochondria-acting drugs in these diseases.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"81 ","pages":"Article 102000"},"PeriodicalIF":3.9,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142813853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The high morbidity and mortality associated with acute kidney injury (AKI) are global health concerns. AKI is commonly attributed to ischemia/reperfusion injury (IRI), a condition characterized by activation of inflammatory responses and mitochondrial dysfunction. Nonetheless, mitochondrial DNA (mtDNA) has the potential to induce renal IRI. This study aimed to elucidate the mechanism and function of mtDNA in HK-2 cells that had been exposed to oxygen-glucose deprivation/reperfusion (OGD/R) and in renal IRI mice. OGD/R was discovered to induce an increase in the amount of mtDNA in HK-2 cells. Moreover, our study demonstrated that mtDNA facilitated cellular apoptosis and inflammation in vivo and in vitro. Given the potential role of inflammation in OGD/R, we investigated the effect of mtDNA on various signaling pathways associated with inflammation. Western blot analysis demonstrated that mtDNA significantly upregulated NLRC5/TAP1 signaling. Furthermore, the upregulation of NLRC5 and TAP1 expression induced by mtDNA was reversed when NLRC5 was inhibited. It is worth mentioning that the loss of NLRC5 effectively nullified the beneficial effects of mtDNA on inflammation and cell apoptosis induced by OGD/R. In addition, in renal IRI mice, mtDNA treatment also aggravated inflammation and kidney damage, and increased the NLRC5 levels in kidney tissues. These results suggested that NLRC5 acts as an intermediary between mtDNA and the pathogenicity of renal IRI. In summary, this study provides evidence that mtDNA promotes apoptosis and inflammation in OGD/R treated HK-2 cells and renal IRI mice through upregulating NLRC5 levels.
{"title":"Mitochondrial DNA (mtDNA) accelerates oxygen-glucose deprivation-induced injury of proximal tubule epithelia cell via inhibiting NLRC5","authors":"Guojun Ge , Bocheng Zhu , Xiaofeng Zhu , Zhenfei Yu , Keqing Zhu , Mengshi Cheng","doi":"10.1016/j.mito.2024.101989","DOIUrl":"10.1016/j.mito.2024.101989","url":null,"abstract":"<div><div>The high morbidity and mortality associated with acute kidney injury (AKI) are global health concerns. AKI is commonly attributed to ischemia/reperfusion injury (IRI), a condition characterized by activation of inflammatory responses and mitochondrial dysfunction. Nonetheless, mitochondrial DNA (mtDNA) has the potential to induce renal IRI. This study aimed to elucidate the mechanism and function of mtDNA in HK-2 cells that had been exposed to oxygen-glucose deprivation/reperfusion (OGD/R) and in renal IRI mice. OGD/R was discovered to induce an increase in the amount of mtDNA in HK-2 cells. Moreover, our study demonstrated that mtDNA facilitated cellular apoptosis and inflammation <em>in vivo</em> and <em>in vitro</em>. Given the potential role of inflammation in OGD/R, we investigated the effect of mtDNA on various signaling pathways associated with inflammation. Western blot analysis demonstrated that mtDNA significantly upregulated <em>NLRC5</em>/<em>TAP1</em> signaling. Furthermore, the upregulation of <em>NLRC5</em> and <em>TAP1</em> expression induced by mtDNA was reversed when <em>NLRC5</em> was inhibited. It is worth mentioning that the loss of <em>NLRC5</em> effectively nullified the beneficial effects of mtDNA on inflammation and cell apoptosis induced by OGD/R. In addition, in renal IRI mice, mtDNA treatment also aggravated inflammation and kidney damage, and increased the <em>NLRC5</em> levels in kidney tissues. These results suggested that <em>NLRC5</em> acts as an intermediary between mtDNA and the pathogenicity of renal IRI. In summary, this study provides evidence that mtDNA promotes apoptosis and inflammation in OGD/R treated HK-2 cells and renal IRI mice through upregulating <em>NLRC5</em> levels.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"81 ","pages":"Article 101989"},"PeriodicalIF":3.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-24DOI: 10.1016/j.mito.2024.101990
Perryn S. Kruth , Chloe MacNeil , John R. Barta
Highly fragmented ribosomal RNA-coding sequences are characteristic of mitogenomes of protozoan parasites of the phylum Apicomplexa. Identification of ribosomal RNA encoding sequences in apicomplexan mitogenomes has largely relied on sequence similarity with several apicomplexan species for which expression of these genes has been demonstrated. The present study applied Next-Gen sequencing to investigate the expression of fragmented putative mitochondrial rRNAs in Eimeria tenella, a coccidian parasite of poultry.
Expression of 18 of 19 putative rDNA fragments included in the original published E. tenella mitogenome was confirmed. Sequence comparison with Plasmodium falciparum and NGS identified 14 additional putative fragments. Two small RNAs were identified that did not share sequence similarities with other known rDNA sequences. Eight sRNAs were identified that represented smaller chunks of putative rDNA fragments and three were observed that represented two putative rDNA fragments (i.e., polycistronic transcripts). Relative abundances of each sRNA species ranged across three orders of magnitude. Twenty-five of the 45 distinct sRNAs expressed from the mitogenome were polyadenylated in more than 50% of instances.
The identification of unique sRNAs without significant homology to known sequences and the observation of polycistronic transcripts highlight the complexity of regulation of expression of the E. tenella mitogenome. The varied relative abundances, presence of shorter RNAs expressed from longer putative rDNA fragments, and variable polyadenylation of these sRNAs highlight additional areas for future work towards better understanding the expression of the mitogenome in this important poultry pathogen. More generally, these findings expand our wider understanding of evolution of apicomplexan mitogenomes.
{"title":"Expression of fragmented ribosomal RNA from the mitochondrial genome of Eimeria tenella","authors":"Perryn S. Kruth , Chloe MacNeil , John R. Barta","doi":"10.1016/j.mito.2024.101990","DOIUrl":"10.1016/j.mito.2024.101990","url":null,"abstract":"<div><div>Highly fragmented ribosomal RNA-coding sequences are characteristic of mitogenomes of protozoan parasites of the phylum Apicomplexa. Identification of ribosomal RNA encoding sequences in apicomplexan mitogenomes has largely relied on sequence similarity with several apicomplexan species for which expression of these genes has been demonstrated. The present study applied Next-Gen sequencing to investigate the expression of fragmented putative mitochondrial rRNAs in<!--> <em>Eimeria tenella</em>, a coccidian parasite of poultry.</div><div>Expression of 18 of 19 putative rDNA fragments included in the original published<!--> <em>E. tenella</em> <!-->mitogenome was confirmed. Sequence comparison with<!--> <em>Plasmodium falciparum</em> <!-->and NGS identified 14 additional putative fragments. Two small RNAs were identified that did not share sequence similarities with other known rDNA sequences. Eight sRNAs were identified that represented smaller chunks of putative rDNA fragments and three were observed that represented two putative rDNA fragments (i.e., polycistronic transcripts). Relative abundances of each sRNA species ranged across three orders of magnitude. Twenty-five of the 45 distinct sRNAs expressed from the mitogenome were polyadenylated in more than 50% of instances.</div><div>The identification of unique sRNAs without significant homology to known sequences and the observation of polycistronic transcripts highlight the complexity of regulation of expression of the<!--> <em>E.<!--> <!-->tenella<!--> </em>mitogenome. The varied relative abundances, presence of shorter RNAs expressed from longer putative rDNA fragments, and variable polyadenylation of these sRNAs highlight additional areas for future work towards better understanding the expression of the mitogenome in this important poultry pathogen. More generally, these findings expand our wider understanding of evolution of apicomplexan mitogenomes.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"81 ","pages":"Article 101990"},"PeriodicalIF":3.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142716271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-24DOI: 10.1016/j.mito.2024.101991
Jiao Luo , Saskia le Cessie , Ko Willems van Dijk , Sara Hägg , Felix Grassmann , Diana van Heemst , Raymond Noordam
Background
Low leukocyte mitochondrial DNA (mtDNA) abundance has been associated with a higher risk of atherosclerotic cardiovascular disease, but through unclear mechanisms. We aimed to investigate whether low mtDNA abundance is associated with worse metabolomic profiling, as being potential intermediate phenotypes, using cross-sectional and genetic studies.
Methods
Among 61,186 unrelated European participants from UK Biobank, we performed multivariable-adjusted linear regression analyses to examine the associations between mtDNA abundance and 168 NMR-based circulating metabolomic measures and nine metabolomic principal components (PCs) that collectively covered 91.5% of the total variation of individual metabolomic measures. Subsequently, we conducted Mendelian randomization (MR) to approximate the causal effects of mtDNA abundance on the individual metabolomic measures and their metabolomic PCs.
Results
After correction for multiple testing, low mtDNA abundance was associated with 130 metabolomic measures, predominantly lower concentrations of some amino acids and higher concentrations of lipids, lipoproteins and fatty acids; moreover, mtDNA abundance was associated with seven out of the nine metabolomic PCs. Using MR, genetically-predicted low mtDNA abundance was associated with lower lactate (standardized beta and 95% confidence interval: −0.17; −0.26, −0.08), and higher acetate (0.15; 0.07,0.23), and unsaturation degree (0.14; 0.08,0.20). Similarly, genetically-predicted low mtDNA abundance was associated with lower metabolomic PC2 (related to lower concentrations of lipids and fatty acids), and higher metabolomic PC9 (related to lower concentrations of glycolysis-related metabolites).
Conclusion
Low mtDNA abundance is associated with metabolomic perturbations, particularly reflecting a pro-atherogenic metabolomic profile, which potentially could link low mtDNA abundance to higher atherosclerosis risk.
{"title":"Mitochondrial DNA abundance and circulating metabolomic profiling: Multivariable-adjusted and Mendelian randomization analyses in UK Biobank","authors":"Jiao Luo , Saskia le Cessie , Ko Willems van Dijk , Sara Hägg , Felix Grassmann , Diana van Heemst , Raymond Noordam","doi":"10.1016/j.mito.2024.101991","DOIUrl":"10.1016/j.mito.2024.101991","url":null,"abstract":"<div><h3>Background</h3><div>Low leukocyte mitochondrial DNA (mtDNA) abundance has been associated with a higher risk of atherosclerotic cardiovascular disease, but through unclear mechanisms. We aimed to investigate whether low mtDNA abundance is associated with worse metabolomic profiling, as being potential intermediate phenotypes, using cross-sectional and genetic studies.</div></div><div><h3>Methods</h3><div>Among 61,186 unrelated European participants from UK Biobank, we performed multivariable-adjusted linear regression analyses to examine the associations between mtDNA abundance and 168 NMR-based circulating metabolomic measures and nine metabolomic principal components (PCs) that collectively covered 91.5% of the total variation of individual metabolomic measures. Subsequently, we conducted Mendelian randomization (MR) to approximate the causal effects of mtDNA abundance on the individual metabolomic measures and their metabolomic PCs.</div></div><div><h3>Results</h3><div>After correction for multiple testing, low mtDNA abundance was associated with 130 metabolomic measures, predominantly lower concentrations of some amino acids and higher concentrations of lipids, lipoproteins and fatty acids; moreover, mtDNA abundance was associated with seven out of the nine metabolomic PCs. Using MR, genetically-predicted low mtDNA abundance was associated with lower lactate (standardized beta and 95% confidence interval: −0.17; −0.26, −0.08), and higher acetate (0.15; 0.07,0.23), and unsaturation degree (0.14; 0.08,0.20). Similarly, genetically-predicted low mtDNA abundance was associated with lower metabolomic PC2 (related to lower concentrations of lipids and fatty acids), and higher metabolomic PC9 (related to lower concentrations of glycolysis-related metabolites).</div></div><div><h3>Conclusion</h3><div>Low mtDNA abundance is associated with metabolomic perturbations, particularly reflecting a pro-atherogenic metabolomic profile, which potentially could link low mtDNA abundance to higher atherosclerosis risk.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"80 ","pages":"Article 101991"},"PeriodicalIF":3.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Genetic control is vital for the growth of cells and tissues, and it also helps living things, from single-celled organisms to complex creatures, maintain a stable internal environment. Within cells, structures called mitochondria act like tiny power plants, producing energy and keeping the cell balanced. The two primary categories of RNA are messenger RNA (mRNA) and non-coding RNA (ncRNA). mRNA carries the instructions for building proteins, while ncRNA does various jobs at the RNA level. There are different kinds of ncRNA, each with a specific role. Some help put RNA molecules together correctly, while others modify other RNAs or cut them into smaller pieces. Still others control how much protein is made from a gene. Scientists have recently discovered many more ncRNAs than previously known, and their functions are still being explored. This article analyzes the RNA molecules present within mitochondria, which have a crucial purpose in the operation of mitochondria. We’ll also discuss how genes can be turned on and off without changing their DNA code, and how this process might be linked to mitochondrial RNA. Finally, we’ll explore how scientists are using engineered particles to silence genes and develop new treatments based on manipulating ncRNA.
{"title":"Scientific investigation of non-coding RNAs in mitochondrial epigenetic and aging disorders: Current nanoengineered approaches for their therapeutic improvement","authors":"Vaibhav Patange , Kailash Ahirwar , Tripti Tripathi , Pratima Tripathi , Rahul Shukla","doi":"10.1016/j.mito.2024.101979","DOIUrl":"10.1016/j.mito.2024.101979","url":null,"abstract":"<div><div>Genetic control is vital for the growth of cells and tissues, and it also helps living things, from single-celled organisms to complex creatures, maintain a stable internal environment. Within cells, structures called mitochondria act like tiny power plants, producing energy and keeping the cell balanced. The two primary categories of RNA are messenger RNA (mRNA) and non-coding RNA (ncRNA). mRNA carries the instructions for building proteins, while ncRNA does various jobs at the RNA level. There are different kinds of ncRNA, each with a specific role. Some help put RNA molecules together correctly, while others modify other RNAs or cut them into smaller pieces. Still others control how much protein is made from a gene. Scientists have recently discovered many more ncRNAs than previously known, and their functions are still being explored. This article analyzes the RNA molecules present within mitochondria, which have a crucial purpose in the operation of mitochondria. We’ll also discuss how genes can be turned on and off without changing their DNA code, and how this process might be linked to mitochondrial RNA. Finally, we’ll explore how scientists are using engineered particles to silence genes and develop new treatments based on manipulating ncRNA.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"80 ","pages":"Article 101979"},"PeriodicalIF":3.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Changes in mitochondrial metabolism produce a malignant transformation from normal cells to tumor cells. Mitochondrial metabolism, comprising bioenergetic metabolism, biosynthetic process, biomolecular decomposition, and metabolic signal conversion, obviously forms a unique sign in the process of tumorigenesis. Several oncometabolites produced by mitochondrial metabolism maintain tumor phenotype, which are recognized as tumor indicators. The mitochondrial metabolism synchronizes the metabolic and genetic outcome to the potent tumor microenvironmental signals, thereby further promoting tumor initiation. Moreover, the bioenergetic and biosynthetic metabolism within tumor mitochondria orchestrates dynamic contributions toward cancer progression and invasion. In this review, we describe the contribution of mitochondrial metabolism in tumorigenesis through shaping several hallmarks such as microenvironment modulation, plasticity, mitochondrial calcium, mitochondrial dynamics, and epithelial-mesenchymal transition. The review will provide a new insight into the abnormal mitochondrial metabolism in tumorigenesis, which will be conducive to tumor prevention and therapy through targeting tumor mitochondria.
{"title":"The multifaceted modulation of mitochondrial metabolism in tumorigenesis","authors":"Keerthiga Rajendiran , Yafang Xie , De-Sheng Pei , Ailing Fu","doi":"10.1016/j.mito.2024.101977","DOIUrl":"10.1016/j.mito.2024.101977","url":null,"abstract":"<div><div>Changes in mitochondrial metabolism produce a malignant transformation from normal cells to tumor cells. Mitochondrial metabolism, comprising bioenergetic metabolism, biosynthetic process, biomolecular decomposition, and metabolic signal conversion, obviously forms a unique sign in the process of tumorigenesis. Several oncometabolites produced by mitochondrial metabolism maintain tumor phenotype, which are recognized as tumor indicators. The mitochondrial metabolism synchronizes the metabolic and genetic outcome to the potent tumor microenvironmental signals, thereby further promoting tumor initiation. Moreover, the bioenergetic and biosynthetic metabolism within tumor mitochondria orchestrates dynamic contributions toward cancer progression and invasion. In this review, we describe the contribution of mitochondrial metabolism in tumorigenesis through shaping several hallmarks such as microenvironment modulation, plasticity, mitochondrial calcium, mitochondrial dynamics, and epithelial-mesenchymal transition. The review will provide a new insight into the abnormal mitochondrial metabolism in tumorigenesis, which will be conducive to tumor prevention and therapy through targeting tumor mitochondria.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"80 ","pages":"Article 101977"},"PeriodicalIF":3.9,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142591232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with succinyl-CoA synthetase (SCS) deficiency caused by pathogenic variants in genes encoding its two subunits. SCS is a mitochondrial enzyme involved in several metabolic pathways and acts as a heterodimer composed of α and β subunits encoded by SUCLG1 and SUCLA2 genes, respectively. The purpose of this study was to analyze the effects of the most pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) by applying, using different prediction tools, a filtering strategy, on the 343 and 365 nsSNPs found in SUCLG1 and SUCLA2 genes, respectively, retrieved from the databases, then to evaluate their structural and functional effects using homology modeling and molecular docking. Results showed that most deleterious mutations selected for structural analysis were located in loop regions critical for protein stability and function, especially, variants altering glycine and proline residues in these regions supporting their importance. We also showed that variants leading to hydrophobic and hydrophilic residues can destabilize the folding and binding of the protein. Molecular docking has also been used to identify the most important regions of ligand binding site (CoA binding site, ADP-Mg2+ binding site and phosphate ion binding site) and between the two subunits themselves, which mainly involving the ligase CoA domain. Our structural analysis, performed on selected nsSNP, are in accordance with experimental studies reported in the literature and predicted that they would responsible to either nonfunctional protein, subunit instability resulting in reduced amounts of misassembled protein, or in a protein unable to phosphorylate ADP.
{"title":"Impact of missense mutations on the structure–function relationship of human succinyl-CoA synthetase using in silico analysis","authors":"Selma Elabed , Olfa Alila Fersi , Abdelaziz Tlili , Ahmed Fendri , Faiza Fakhfakh","doi":"10.1016/j.mito.2024.101978","DOIUrl":"10.1016/j.mito.2024.101978","url":null,"abstract":"<div><div>The encephalomyopathic mtDNA depletion syndrome with methylmalonic aciduria is associated with succinyl-CoA synthetase (SCS) deficiency caused by pathogenic variants in genes encoding its two subunits. SCS is a mitochondrial enzyme involved in several metabolic pathways and acts as a heterodimer composed of α and β subunits encoded by <em>SUCLG1</em> and <em>SUCLA2</em> genes, respectively. The purpose of this study was to analyze the effects of the most pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) by applying, using different prediction tools, a filtering strategy, on the 343 and 365 nsSNPs found in <em>SUCLG1</em> and <em>SUCLA2</em> genes, respectively, retrieved from the databases, then to evaluate their structural and functional effects using homology modeling and molecular docking. Results showed that most deleterious mutations selected for structural analysis were located in loop regions critical for protein stability and function, especially, variants altering glycine and proline residues in these regions supporting their importance. We also showed that variants leading to hydrophobic and hydrophilic residues can destabilize the folding and binding of the protein. Molecular docking has also been used to identify the most important regions of ligand binding site (CoA binding site, ADP-Mg<sup>2+</sup> binding site and phosphate ion binding site) and between the two subunits themselves, which mainly involving the ligase CoA domain. Our structural analysis, performed on selected nsSNP, are in accordance with experimental studies reported in the literature and predicted that they would responsible to either nonfunctional protein, subunit instability resulting in reduced amounts of misassembled protein, or in a protein unable to phosphorylate ADP.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"80 ","pages":"Article 101978"},"PeriodicalIF":3.9,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142580946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. Recent advances in immunometabolism have revealed the pivotal role of mitochondrial dynamics and metabolism in shaping Treg functionality. Tregs depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to support their suppressive functions and long-term survival. Mitochondrial processes such as fusion and fission significantly influence Treg activity, with mitochondrial fusion enhancing bioenergetic efficiency and reducing reactive oxygen species (ROS) production, thereby promoting Treg stability. In contrast, excessive mitochondrial fission disrupts ATP synthesis and elevates ROS levels, impairing Treg suppressive capacity. Furthermore, mitochondrial ROS act as critical signaling molecules in Treg regulation, where controlled levels stabilize FoxP3 expression, but excessive ROS leads to mitochondrial dysfunction and immune dysregulation. Mitophagy, as part of mitochondrial quality control, also plays an essential role in preserving Treg function. Understanding the intricate interplay between mitochondrial dynamics and Treg metabolism provides valuable insights for developing novel therapeutic strategies to treat autoimmune disorders and enhance immunotherapy in cancer.
{"title":"Mitochondrial mechanisms in Treg cell regulation: Implications for immunotherapy and disease treatment","authors":"Xiaozhen Zhao, Junmei Zhang, Caifeng Li, Weiying Kuang, Jianghong Deng, Xiaohua Tan, Chao Li, Shipeng Li","doi":"10.1016/j.mito.2024.101975","DOIUrl":"10.1016/j.mito.2024.101975","url":null,"abstract":"<div><div>Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. Recent advances in immunometabolism have revealed the pivotal role of mitochondrial dynamics and metabolism in shaping Treg functionality. Tregs depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to support their suppressive functions and long-term survival. Mitochondrial processes such as fusion and fission significantly influence Treg activity, with mitochondrial fusion enhancing bioenergetic efficiency and reducing reactive oxygen species (ROS) production, thereby promoting Treg stability. In contrast, excessive mitochondrial fission disrupts ATP synthesis and elevates ROS levels, impairing Treg suppressive capacity. Furthermore, mitochondrial ROS act as critical signaling molecules in Treg regulation, where controlled levels stabilize FoxP3 expression, but excessive ROS leads to mitochondrial dysfunction and immune dysregulation. Mitophagy, as part of mitochondrial quality control, also plays an essential role in preserving Treg function. Understanding the intricate interplay between mitochondrial dynamics and Treg metabolism provides valuable insights for developing novel therapeutic strategies to treat autoimmune disorders and enhance immunotherapy in cancer.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"80 ","pages":"Article 101975"},"PeriodicalIF":3.9,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.mito.2024.101976
Frédérique Paquin , Melania E. Cristescu , Pierre U. Blier , Hélène Lemieux , France Dufresne
The impact of mutations on the mitochondria deserves specific interest due to the crucial role played by these organelles on numerous cellular functions. This study examines the effects of repeated bottlenecks on mitochondrial function and fitness. Daphnia pulex mutation accumulation lines (MA) lines were maintained for over 120 generations under copper and no copper conditions. Following the MA propagation, Daphnia from MA lines were raised under optimal and high temperatures for two generations before assessing mitochondrial and phenotypic traits. Spontaneous mutation accumulation under copper led to a later age at maturity and lowered fecundity in the MA lines. Mitochondrial respiration was found to be 10% lower in all mutation accumulation (MA) lines as compared to the non-MA control. MtDNA copy number was elevated in MA lines compared to the control under optimal temperature suggesting a compensatory mechanism. Three MA lines propagated under low copper had very low mtDNA copy number and fitness, suggesting mutations might have affected genes involved in mtDNA replication or mitochondrial biogenesis. Overall, our study suggests that mutation accumulation had an impact on life history traits, mtDNA copy number, and mitochondrial respiration. Some phenotypic effects were magnified under high temperatures. MtDNA copy number appears to be an important mitigation factor to allow mitochondria to cope with mutation accumulation up to a certain level beyond which it can no longer compensate.
突变对线粒体的影响值得特别关注，因为这些细胞器对许多细胞功能起着至关重要的作用。本研究探讨了重复瓶颈对线粒体功能和适应性的影响。水蚤突变积累系（MA）在有铜和无铜条件下维持了 120 多代。突变积累品系繁殖后，将突变积累品系的水蚤在最适温度和高温条件下饲养两代，然后评估线粒体和表型特征。铜条件下的自发突变积累导致 MA 品系的成熟年龄推迟，繁殖力降低。与非突变积累（MA）对照相比，所有突变积累（MA）品系的线粒体呼吸都降低了 10%。在最适温度下，MA品系的MtDNA拷贝数比对照高，这表明存在补偿机制。在低铜条件下繁殖的三个 MA 株系的 mtDNA 拷贝数和适应性都很低，这表明突变可能影响了参与 mtDNA 复制或线粒体生物发生的基因。总之，我们的研究表明，突变积累对生活史特征、mtDNA拷贝数和线粒体呼吸都有影响。在高温条件下，一些表型效应被放大。MtDNA拷贝数似乎是一个重要的缓解因素，可使线粒体应对突变积累，但当突变积累达到一定程度后，线粒体就无法再进行补偿。
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