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。
{"title":"Cumulative effects of mutation accumulation on mitochondrial function and fitness","authors":"Frédérique Paquin , Melania E. Cristescu , Pierre U. Blier , Hélène Lemieux , France Dufresne","doi":"10.1016/j.mito.2024.101976","DOIUrl":"10.1016/j.mito.2024.101976","url":null,"abstract":"<div><div>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. <em>Daphnia pulex</em> mutation accumulation lines (MA) lines were maintained for over 120 generations under copper and no copper conditions. Following the MA propagation, <em>Daphnia</em> 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.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"80 ","pages":"Article 101976"},"PeriodicalIF":3.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563611","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}
Pub Date : 2024-10-24DOI: 10.1016/j.mito.2024.101974
Lei Tian , Qian Liu , Hong Guo , Honggang Zang , Yulan Li
Ischemia-reperfusion injury (IRI) is a major cause of mortality and morbidity. Current treatments for IRI have limited efficacy and novel therapeutic strategies are needed. Mitochondrial dysfunction not only initiates IRI but also plays a significant role in ferroptosis pathogenesis. Recent studies have highlighted that targeting mitochondrial pathways is a promising therapeutic approach for ferroptosis-induced IRI. The association between ferroptosis and IRI has been reviewed many times, but our review provides the first comprehensive overview with a focus on recent mitochondrial research. First, we present the role of mitochondria in ferroptosis. Then, we summarize the evidence on mitochondrial manipulation of ferroptosis in IRI and review recent therapeutic strategies aimed at targeting mitochondria-related ferroptosis to mitigate IRI. We hope our review will provide new ideas for the treatment of IRI and accelerate the transition from bench to bedside.
缺血再灌注损伤（IRI）是导致死亡和发病的主要原因。目前治疗 IRI 的方法疗效有限，需要新的治疗策略。线粒体功能障碍不仅会引发 IRI，而且在铁变态反应发病机制中也起着重要作用。最近的研究强调，针对线粒体通路是治疗铁变态反应诱导的 IRI 的一种很有前景的方法。有关铁变态反应与 IRI 之间的关系已被多次综述，但我们的综述是首次以线粒体的最新研究为重点进行的全面综述。首先，我们介绍了线粒体在铁中毒中的作用。然后，我们总结了线粒体在 IRI 中操纵铁蛋白沉积的证据，并回顾了近期针对线粒体相关铁蛋白沉积以缓解 IRI 的治疗策略。我们希望我们的综述能为 IRI 的治疗提供新思路，并加速从实验室到临床的转变。
{"title":"Fighting ischemia-reperfusion injury: Focusing on mitochondria-derived ferroptosis","authors":"Lei Tian , Qian Liu , Hong Guo , Honggang Zang , Yulan Li","doi":"10.1016/j.mito.2024.101974","DOIUrl":"10.1016/j.mito.2024.101974","url":null,"abstract":"<div><div>Ischemia-reperfusion injury (IRI) is a major cause of mortality and morbidity. Current treatments for IRI have limited efficacy and novel therapeutic strategies are needed. Mitochondrial dysfunction not only initiates IRI but also plays a significant role in ferroptosis pathogenesis. Recent studies have highlighted that targeting mitochondrial pathways is a promising therapeutic approach for ferroptosis-induced IRI. The association between ferroptosis and IRI has been reviewed many times, but our review provides the first comprehensive overview with a focus on recent mitochondrial research. First, we present the role of mitochondria in ferroptosis. Then, we summarize the evidence on mitochondrial manipulation of ferroptosis in IRI and review recent therapeutic strategies aimed at targeting mitochondria-related ferroptosis to mitigate IRI. We hope our review will provide new ideas for the treatment of IRI and accelerate the transition from bench to bedside.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"79 ","pages":"Article 101974"},"PeriodicalIF":3.9,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504015","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 : 2024-10-15DOI: 10.1016/j.mito.2024.101973
Rodrigo T. Starosta , Austin A. Larson , Naomi J.L. Meeks , Sara Gracie , Marisa W. Friederich , Sommer M. Gaughan , Peter R. Baker II , Kelly G. Knupp , Cole R. Michel , Richard Reisdorph , Daniella H. Hock , David A. Stroud , Tim Wood , Johan L.K. Van Hove
The diagnosis of mitochondrial disorders is complex. Rapid whole genome sequencing is a first line test for critically ill neonates and infants allowing rapid diagnosis and treatment. Standard genomic technology and bioinformatic pipelines still have an incomplete diagnostic yield requiring complementary approaches. There are currently limited options for rapid additional tests to continue a diagnostic work-up after a negative rapid whole-genome sequencing result, reflecting a gap in clinical practice. Multi-modal integrative diagnostic approaches derived from systems biology including proteomics and transcriptomics show promise in suspected mitochondrial disorders. In this article, we report the case of a neonate who presented with severe lactic acidosis on the second day of life, for whom an initial report of ultra-rapid genome sequencing was negative. The patient was started on dichloroacetate as an emergency investigational new drug (eIND), with a sharp decline in lactic acid levels and clinical stabilization. A proteomics-based approach identified a complete absence of PDHX protein, leading to a re-review of the genome data for the PDHX gene in which a homozygous deep intronic pathogenic variant was identified. Subsequent testing in the following months confirmed the diagnosis with deficient pyruvate dehydrogenase enzyme activity, reduced protein levels of E3-binding protein, and confirmed by mRNA sequencing to lead to the inclusion of a cryptic exon and a premature stop codon. This case highlights the power of rapid proteomics in guiding genomic analysis. It also shows a promising role for dichloroacetate treatment in controlling lactic acidosis related to PDHX-related pyruvate dehydrogenase complex deficiency.
{"title":"An integrated multi-omics approach allowed ultra-rapid diagnosis of a deep intronic pathogenic variant in PDHX and precision treatment in a neonate critically ill with lactic acidosis","authors":"Rodrigo T. Starosta , Austin A. Larson , Naomi J.L. Meeks , Sara Gracie , Marisa W. Friederich , Sommer M. Gaughan , Peter R. Baker II , Kelly G. Knupp , Cole R. Michel , Richard Reisdorph , Daniella H. Hock , David A. Stroud , Tim Wood , Johan L.K. Van Hove","doi":"10.1016/j.mito.2024.101973","DOIUrl":"10.1016/j.mito.2024.101973","url":null,"abstract":"<div><div>The diagnosis of mitochondrial disorders is complex. Rapid whole genome sequencing is a first line test for critically ill neonates and infants allowing rapid diagnosis and treatment. Standard genomic technology and bioinformatic pipelines still have an incomplete diagnostic yield requiring complementary approaches. There are currently limited options for rapid additional tests to continue a diagnostic work-up after a negative rapid whole-genome sequencing result, reflecting a gap in clinical practice. Multi-modal integrative diagnostic approaches derived from systems biology including proteomics and transcriptomics show promise in suspected mitochondrial disorders. In this article, we report the case of a neonate who presented with severe lactic acidosis on the second day of life, for whom an initial report of ultra-rapid genome sequencing was negative. The patient was started on dichloroacetate as an emergency investigational new drug (eIND), with a sharp decline in lactic acid levels and clinical stabilization. A proteomics-based approach identified a complete absence of PDHX protein, leading to a re-review of the genome data for the <em>PDHX</em> gene in which a homozygous deep intronic pathogenic variant was identified. Subsequent testing in the following months confirmed the diagnosis with deficient pyruvate dehydrogenase enzyme activity, reduced protein levels of E3-binding protein, and confirmed by mRNA sequencing to lead to the inclusion of a cryptic exon and a premature stop codon. This case highlights the power of rapid proteomics in guiding genomic analysis. It also shows a promising role for dichloroacetate treatment in controlling lactic acidosis related to <em>PDHX</em>-related pyruvate dehydrogenase complex deficiency.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"79 ","pages":"Article 101973"},"PeriodicalIF":3.9,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469820","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 : 2024-10-02DOI: 10.1016/j.mito.2024.101972
Keshari Sriwastawa, Ashutosh Kumar
Diabetic neuropathy is one of the challenging complications of diabetes and is characterized by peripheral nerve damage due to hyperglycemia in diabetes. Mitochondrial dysfunction has been reported as one of the key pathophysiological factor contributing to nerve damage in diabetic neuropathy, clinically manifesting as neurodegenerative changes like functional and sensorimotor deficits. Accumulating evidence suggests a clear correlation between mitochondrial dysfunction and NLRP3 inflammasome activation. Unraveling deeper molecular aspects of mitochondrial dysfunction may provide safer and effective therapeutic alternatives. This review links mitochondrial dysfunction and appraises its role in the pathophysiology of diabetic neuropathy. We have also tried to delineate the role of mitophagy in NLRP3 inflammasome activation in experimental diabetic neuropathy.
{"title":"Mitochondrial dysfunction in diabetic neuropathy: Impaired mitophagy triggers NLRP3 inflammasome","authors":"Keshari Sriwastawa, Ashutosh Kumar","doi":"10.1016/j.mito.2024.101972","DOIUrl":"10.1016/j.mito.2024.101972","url":null,"abstract":"<div><div>Diabetic neuropathy is one of the challenging complications of diabetes and is characterized by peripheral nerve damage due to hyperglycemia in diabetes. Mitochondrial dysfunction has been reported as one of the key pathophysiological factor contributing to nerve damage in diabetic neuropathy, clinically manifesting as neurodegenerative changes like functional and sensorimotor deficits. Accumulating evidence suggests a clear correlation between mitochondrial dysfunction and NLRP3 inflammasome activation. Unraveling deeper molecular aspects of mitochondrial dysfunction may provide safer and effective therapeutic alternatives. This review links mitochondrial dysfunction and appraises its role in the pathophysiology of diabetic neuropathy. We have also tried to delineate the role of mitophagy in NLRP3 inflammasome activation in experimental diabetic neuropathy.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"79 ","pages":"Article 101972"},"PeriodicalIF":3.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372312","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 : 2024-09-30DOI: 10.1016/j.mito.2024.101971
Chinmay Pal
Parkinson’s disease (PD), a neurodegenerative disorder, is one of the most significant challenges confronting modern societies, affecting millions of patients globally each year. The pathophysiology of PD is significantly influenced by mitochondrial dysfunction, as evident by the contribution of altered mitochondrial dynamics, bioenergetics, and increased oxidative stress to neuronal death. This review examines the potential use of small molecules that target mitochondria as a therapeutic approach for treating PD. Progress in mitochondrial biology has revealed various mitochondrial targets that can be modulated to restore function and mitigate neurodegeneration. Small molecules that promote mitochondrial biogenesis, enhance mitochondrial dynamics, decrease oxidative stress, and prevent the opening of the mitochondrial permeability transition pore (mPTP) have shown promise in preclinical models. Additionally, targeting mitochondrial quality control mechanisms, such as mitophagy, provides another therapeutic approach. This review explores recent research on small molecules targeting mitochondria, examines their mechanisms of action, and assesses their potential efficacy and safety profiles. By highlighting the most promising candidates and addressing the challenges and future directions in this field, this review aims to offer a comprehensive overview of current and future prospects for mitochondrial-targeted therapies in PD. Ultimately, treating mitochondrial dysfunction holds significant promise for developing disease-modifying PD medications, giving patients hope for better outcomes and improved quality of life.
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Pub Date : 2024-09-28DOI: 10.1016/j.mito.2024.101967
Bushra , Shaik Iqbal Ahmed , Safia Begum , Maaria , Mohammed Safwaan Habeeb , Tahmeen Jameel , Aleem Ahmed Khan
Sepsis remains a critical challenge in the field of medicine, claiming countless lives each year. Despite significant advances in medical science, the molecular mechanisms underlying sepsis pathogenesis remain elusive. Understanding molecular sequelae is gaining deeper insights into the roles played by various damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) in disease pathogenesis. Among the known DAMPs, circulating cell-free mitochondrial DNA (mtDNA) garners increasing attention as a key player in the immune response during sepsis and other diseases. Mounting evidence highlights numerous connections between circulating cell-free mtDNA and inflammation, a pivotal state of sepsis, characterized by heightened inflammatory activity. In this review, we aim to provide an overview of the molecular basis of sepsis, particularly emphasizing the role of circulating cell-free mtDNA as a DAMP. We discuss the mechanisms of mtDNA release, its interaction with pattern recognition receptors (PRRs), and the subsequent immunological responses that contribute to sepsis progression. Furthermore, we discuss the forms of cell-free mtDNA; detection techniques of circulating cell-free mtDNA in various biological fluids; and the diagnostic, prognostic, and therapeutic implications offering insights into the potential for innovative interventions in sepsis management.
{"title":"Molecular basis of sepsis: A New insight into the role of mitochondrial DNA as a damage-associated molecular pattern","authors":"Bushra , Shaik Iqbal Ahmed , Safia Begum , Maaria , Mohammed Safwaan Habeeb , Tahmeen Jameel , Aleem Ahmed Khan","doi":"10.1016/j.mito.2024.101967","DOIUrl":"10.1016/j.mito.2024.101967","url":null,"abstract":"<div><div>Sepsis remains a critical challenge in the field of medicine, claiming countless lives each year. Despite significant advances in medical science, the molecular mechanisms underlying sepsis pathogenesis remain elusive. Understanding molecular sequelae is gaining deeper insights into the roles played by various damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) in disease pathogenesis. Among the known DAMPs, circulating cell-free mitochondrial DNA (mtDNA) garners increasing attention as a key player in the immune response during sepsis and other diseases. Mounting evidence highlights numerous connections between circulating cell-free mtDNA and inflammation, a pivotal state of sepsis, characterized by heightened inflammatory activity. In this review, we aim to provide an overview of the molecular basis of sepsis, particularly emphasizing the role of circulating cell-free mtDNA as a DAMP. We discuss the mechanisms of mtDNA release, its interaction with pattern recognition receptors (PRRs), and the subsequent immunological responses that contribute to sepsis progression. Furthermore, we discuss the forms of cell-free mtDNA; detection techniques of circulating cell-free mtDNA in various biological fluids; and the diagnostic, prognostic, and therapeutic implications offering insights into the potential for innovative interventions in sepsis management.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"79 ","pages":"Article 101967"},"PeriodicalIF":3.9,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350002","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}
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