Mitochondrion最新文献_第10页

Cumulative effects of mutation accumulation on mitochondrial function and fitness 突变积累对线粒体功能和健康的累积效应。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-10-31 DOI: 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}

引用次数: 0

Fighting ischemia-reperfusion injury: Focusing on mitochondria-derived ferroptosis 抗击缺血再灌注损伤：关注线粒体衍生的铁变态反应。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-10-24 DOI: 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。

引用次数: 0

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 通过多组学集成方法，超快速诊断出PDHX的深层内含致病变体，并对一名患有乳酸酸中毒的重症新生儿进行了精准治疗。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-10-15 DOI: 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.

线粒体疾病的诊断非常复杂。快速全基因组测序是重症新生儿和婴儿的一线检测方法，可用于快速诊断和治疗。标准基因组技术和生物信息学管道的诊断结果仍不全面，需要补充方法。目前，在快速全基因组测序结果呈阴性后，继续进行诊断工作的快速附加测试选择有限，这反映了临床实践中的差距。来自系统生物学（包括蛋白质组学和转录组学）的多模式综合诊断方法在疑似线粒体疾病中大有可为。在本文中，我们报告了一例新生儿的病例，该新生儿在出生后第二天出现严重乳酸酸中毒，超快速基因组测序的初步报告为阴性。作为一种紧急研究新药（eIND），患者开始服用二氯乙酸，随后乳酸水平急剧下降，临床症状趋于稳定。基于蛋白质组学的方法确定了 PDHX 蛋白的完全缺失，从而重新审查了 PDHX 基因的基因组数据，并在其中发现了一个同卵深内含子致病变体。随后几个月的检测证实了这一诊断，丙酮酸脱氢酶酶活性不足，E3结合蛋白水平降低，mRNA测序证实其中包含一个隐性外显子和一个过早终止密码子。该病例凸显了快速蛋白质组学在指导基因组分析方面的作用。它还显示了二氯乙酸治疗在控制与 PDHX 相关的丙酮酸脱氢酶复合物缺乏症有关的乳酸酸中毒方面的作用。

{"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}

引用次数: 0

Mitochondrial dysfunction in diabetic neuropathy: Impaired mitophagy triggers NLRP3 inflammasome 糖尿病神经病变中的线粒体功能障碍：丝裂噬功能受损引发 NLRP3 炎性体。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-10-02 DOI: 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.

糖尿病神经病变是具有挑战性的糖尿病并发症之一，其特征是糖尿病高血糖导致的周围神经损伤。据报道，线粒体功能障碍是导致糖尿病神经病变中神经损伤的关键病理生理因素，临床表现为神经退行性病变以及功能和感觉运动障碍。越来越多的证据表明，线粒体功能障碍与 NLRP3 炎症小体激活之间存在明显的相关性。揭示线粒体功能障碍更深层次的分子方面可能会提供稳定有效的替代治疗方法。本综述将线粒体功能障碍联系起来，并评估其在糖尿病神经病变的病理生理学中的作用。我们还试图阐明线粒体吞噬在实验性糖尿病神经病变中激活 NLRP3 炎性体的作用。

引用次数: 0

Targeting mitochondria with small molecules: A promising strategy for combating Parkinson’s disease 用小分子靶向线粒体：抗击帕金森病的有效策略

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-09-30 DOI: 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.

帕金森病（PD）是一种神经退行性疾病，是现代社会面临的最重大挑战之一，每年影响全球数百万患者。帕金森病的病理生理学受到线粒体功能障碍的显著影响，线粒体动力学、生物能量学的改变以及氧化应激的增加对神经元死亡的贡献就证明了这一点。本综述探讨了以线粒体为靶点的小分子药物作为治疗帕金森病的一种治疗方法的潜在用途。线粒体生物学的研究进展揭示了各种线粒体靶点，通过调节这些靶点可以恢复线粒体功能并减轻神经退行性变。促进线粒体生物生成、增强线粒体活力、减少氧化应激和防止线粒体通透性转换孔（mPTP）开放的小分子药物已在临床前模型中显示出前景。此外，针对线粒体质量控制机制（如有丝分裂）的研究也提供了另一种治疗方法。本综述探讨了针对线粒体的小分子药物的最新研究，研究了它们的作用机制，并评估了它们的潜在疗效和安全性。通过强调最有希望的候选药物并探讨该领域的挑战和未来方向，本综述旨在全面概述线粒体靶向治疗帕金森病的当前和未来前景。最终，治疗线粒体功能障碍为开发改变帕金森病病情的药物带来了巨大希望，使患者有望获得更好的治疗效果并改善生活质量。

{"title":"Targeting mitochondria with small molecules: A promising strategy for combating Parkinson’s disease","authors":"Chinmay Pal","doi":"10.1016/j.mito.2024.101971","DOIUrl":"10.1016/j.mito.2024.101971","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"79 ","pages":"Article 101971"},"PeriodicalIF":3.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365820","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}

引用次数: 0

Molecular basis of sepsis: A New insight into the role of mitochondrial DNA as a damage-associated molecular pattern 败血症的分子基础：线粒体 DNA 作为损伤相关分子模式作用的新见解。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-09-28 DOI: 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.

败血症仍然是医学领域的一项重大挑战，每年夺去无数人的生命。尽管医学科学取得了重大进展，但脓毒症发病的分子机制仍然难以捉摸。通过对分子后遗症的了解，人们对各种损伤相关分子模式（DAMPs）和病原体相关分子模式（PAMPs）在疾病发病机制中的作用有了更深入的认识。在已知的 DAMPs 中，循环细胞游离线粒体 DNA（mtDNA）在败血症和其他疾病的免疫反应中发挥着关键作用，因而日益受到关注。越来越多的证据表明，循环细胞游离线粒体 DNA 与炎症（脓毒症的一种关键状态，其特点是炎症活动加剧）之间存在诸多联系。在这篇综述中，我们旨在概述败血症的分子基础，特别强调循环细胞游离 mtDNA 作为 DAMP 的作用。我们讨论了 mtDNA 的释放机制、其与模式识别受体 (PRR) 的相互作用以及随后导致败血症进展的免疫反应。此外，我们还讨论了游离细胞 mtDNA 的形式；各种生物液体中循环游离细胞 mtDNA 的检测技术；以及诊断、预后和治疗方面的影响，为脓毒症治疗中创新干预措施的潜力提供了启示。

{"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}

引用次数: 0

The maternal genetic history of tribal populations of Chhattisgarh, India 印度恰蒂斯加尔邦部落人口的孕产史。

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-09-26 DOI: 10.1016/j.mito.2024.101970

Shivani Dixit , Pankaj Shrivastava , Jaison Jeevan Sequeira , Mohammed S Mustak , Manisha Rana , Pushpesh Kushwaha , Divya Shrivastava , R.K. Kumawat , Prajjval Pratap Singh , Sachin K. Tiwary , Neeraj K. Chauhan , Gyaneshwer Chaubey

The central region of India boasts a rich tribal heritage and the highest number of tribal populations in the country. Analysing the genetic history of this population can offer valuable insights into various demographic processes that shaped the gene pool of present-day settlers of this region. In this study, we utilize a recently validated Next-generation sequencing (NGS) technique to sequence 24 tribal mitogenomes from the Chhattisgarh population for genetic ancestry and forensic analysis. The identified ancient haplogroups in this population can be traced back to the pre-Last Glacial Maximum (LGM) period. Our Bayesian analysis provides evidence for maternal ancestral expansion following the earliest Out-of-Africa migration, followed by a prolonged steady phase. We identified three basal founding haplogroups, M2, R5, and U2 in the Chhattisgarh region that diversified during the Neolithic period. Indistinct distribution pattern of these haplogroups among tribes and castes suggests that the maternal ancestry of Chhattisgarh population predates any kind of social stratification that exists today in the Indian subcontinent. Furthermore, our analysis suggests that this region remained unaffected by the Last Glacial Maximum. The forensic analysis of the mitogenomes demonstrates a high power of discrimination (0.9256) within the Chhattisgarh population, thus supporting the applicability of mitogenome NGS technology in forensic contexts.

印度中部地区拥有丰富的部落遗产，是印度部落人口最多的地区。对这一人口的遗传历史进行分析，可以为了解塑造该地区当今定居者基因库的各种人口过程提供有价值的信息。在本研究中，我们利用最新验证的下一代测序（NGS）技术对恰蒂斯加尔邦人口中的 24 个部落有丝分裂基因组进行测序，以进行遗传祖先和法医分析。在这一人群中发现的古老单倍群可追溯到末次冰川极盛期（LGM）之前。我们的贝叶斯分析为最早的非洲外迁后的母系祖先扩张提供了证据，随后是一个长期的稳定阶段，直到全新世的人口下降。我们在恰蒂斯加尔地区发现了三个基本的创始单倍群，即 M2、R5 和 U2，这些单倍群在新石器时代发生了分化。这些单倍群在部落和种姓中的分布模式不明显，这表明恰蒂斯加尔人口的母系祖先早于印度次大陆今天存在的任何社会分层。此外，我们的分析表明，该地区未受到末次冰川大期的影响。对有丝分裂基因组的法医分析表明，恰蒂斯加尔邦人口的鉴别力很高（0.9256），因此支持有丝分裂基因组 NGS 技术在法医方面的应用。

{"title":"The maternal genetic history of tribal populations of Chhattisgarh, India","authors":"Shivani Dixit , Pankaj Shrivastava , Jaison Jeevan Sequeira , Mohammed S Mustak , Manisha Rana , Pushpesh Kushwaha , Divya Shrivastava , R.K. Kumawat , Prajjval Pratap Singh , Sachin K. Tiwary , Neeraj K. Chauhan , Gyaneshwer Chaubey","doi":"10.1016/j.mito.2024.101970","DOIUrl":"10.1016/j.mito.2024.101970","url":null,"abstract":"<div><div>The central region of India boasts a rich tribal heritage and the highest number of tribal populations in the country. Analysing the genetic history of this population can offer valuable insights into various demographic processes that shaped the gene pool of present-day settlers of this region. In this study, we utilize a recently validated Next-generation sequencing (NGS) technique to sequence 24 tribal mitogenomes from the Chhattisgarh population for genetic ancestry and forensic analysis. The identified ancient haplogroups in this population can be traced back to the pre-Last Glacial Maximum (LGM) period. Our Bayesian analysis provides evidence for maternal ancestral expansion following the earliest Out-of-Africa migration, followed by a prolonged steady phase. We identified three basal founding haplogroups, M2, R5, and U2 in the Chhattisgarh region that diversified during the Neolithic period. Indistinct distribution pattern of these haplogroups among tribes and castes suggests that the maternal ancestry of Chhattisgarh population predates any kind of social stratification that exists today in the Indian subcontinent. Furthermore, our analysis suggests that this region remained unaffected by the Last Glacial Maximum. The forensic analysis of the mitogenomes demonstrates a high power of discrimination (0.9256) within the Chhattisgarh population, thus supporting the applicability of mitogenome NGS technology in forensic contexts.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"79 ","pages":"Article 101970"},"PeriodicalIF":3.9,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350003","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}

引用次数: 0

Mitochondrial genome-derived circRNAs: Orphan epigenetic regulators in molecular biology 线粒体基因组衍生的 circRNA：分子生物学中的 "孤儿 "表观遗传调节因子

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-09-23 DOI: 10.1016/j.mito.2024.101968

Nima Sanadgol , Javad Amini , Roghayeh Khalseh , Mostafa Bakhshi , Arezoo Nikbin , Cordian Beyer , Adib Zendehdel

Mitochondria are vital for cellular activities, influencing ATP production, Ca2⁺ signaling, and reactive oxygen species generation. It has been proposed that nuclear genome-derived circular RNAs (circRNAs) play a role in biological processes. For the first time, this study aims to comprehensively explore experimentally confirmed human mitochondrial genome-derived circRNAs (mt-circRNAs) via in-silico analysis. We utilized wide-ranging bioinformatics tools to anticipate their roles in molecular biology, involving miRNA sponging, protein antagonism, and peptide translation. Among five well-characterized mt-circRNAs, SCAR/mc-COX2 stands out as particularly significant with the potential to sponge around 41 different miRNAs, which target several genes mostly involved in endocytosis, MAP kinase, and PI3K-Akt pathways. Interestingly, circMNTND5 and mecciND1 specifically interact with miRNAs through their unique back-splice junction sequence. These exclusively targeted miRNAs (has-miR-5186, 6888-5p, 8081, 924, 672-5p) are predominantly associated with insulin secretion, proteoglycans in cancer, and MAPK signaling pathways. Moreover, all mt-circRNAs intricately affect the P53 pathway through miRNA sequestration. Remarkably, mc-COX2 and circMNTND5 appear to be involved in the RNA’s biogenesis by antagonizing AGO1/2, EIF4A3, and DGCR8. All mt-circRNAs engaged with IGF2BP proteins crucial in redox signaling, and except mecciND1, they all potentially generate at least one protein resembling the immunoglobulin heavy chain protein. Given P53′s function as a redox-sensitive transcription factor, and insulin’s role as a crucial regulator of energy metabolism, their indirect interplay with mt-circRNAs could influence cellular outcomes. However, due to limited attention and infrequent data availability, it is advisable to conduct more thorough investigations to gain a deeper understanding of the functions of mt-circRNA.

线粒体对细胞活动至关重要，影响着 ATP 生成、Ca2+ 信号传导和活性氧生成。有人提出，核基因组衍生的环状 RNA（circRNA）在生物过程中发挥作用。本研究首次旨在通过内嵌分析，全面探索经实验证实的人类线粒体基因组衍生的环状核糖核酸（mt-circRNAs）。我们利用广泛的生物信息学工具来预测它们在分子生物学中的作用，包括 miRNA 海绵作用、蛋白质拮抗作用和肽翻译作用。在五种表征明确的mt-circRNA中，SCAR/mc-COX2尤为突出，它具有海绵状作用的潜力，可吸附约41种不同的miRNA，这些miRNA主要靶向参与内吞、MAP激酶和PI3K-Akt通路的多个基因。有趣的是，circMNTND5 和 mecciND1 通过其独特的后接合序列与 miRNA 发生特异性相互作用。这些专门靶向的 miRNA（has-miR-5186、6888-5p、8081、924、672-5p）主要与胰岛素分泌、癌症中的蛋白多糖和 MAPK 信号通路有关。此外，所有 mt-circRNA 都会通过 miRNA 封存作用对 P53 通路产生错综复杂的影响。值得注意的是，mc-COX2 和 circMNTND5 似乎通过拮抗 AGO1/2、EIF4A3 和 DGCR8 参与了 RNA 的生物发生。所有 mt-circRNA 都与氧化还原信号转导中至关重要的 IGF2BP 蛋白相互作用，除 mecciND1 外，它们都可能生成至少一种类似免疫球蛋白重链蛋白的蛋白质。鉴于 P53 具有氧化还原敏感转录因子的功能，而胰岛素是能量代谢的关键调节因子，它们与 mt-circRNA 的间接相互作用可能会影响细胞的结果。然而，由于关注度有限和数据不经常获得，最好进行更深入的研究，以更深入地了解 mt-circRNA 的功能。

{"title":"Mitochondrial genome-derived circRNAs: Orphan epigenetic regulators in molecular biology","authors":"Nima Sanadgol , Javad Amini , Roghayeh Khalseh , Mostafa Bakhshi , Arezoo Nikbin , Cordian Beyer , Adib Zendehdel","doi":"10.1016/j.mito.2024.101968","DOIUrl":"10.1016/j.mito.2024.101968","url":null,"abstract":"<div><div>Mitochondria are vital for cellular activities, influencing ATP production, Ca2<sup>+</sup> signaling, and reactive oxygen species generation. It has been proposed that nuclear genome-derived circular RNAs (circRNAs) play a role in biological processes. For the first time, this study aims to comprehensively explore experimentally confirmed human mitochondrial genome-derived circRNAs (mt-circRNAs) via in-silico analysis. We utilized wide-ranging bioinformatics tools to anticipate their roles in molecular biology, involving miRNA sponging, protein antagonism, and peptide translation. Among five well-characterized mt-circRNAs, SCAR/mc-COX2 stands out as particularly significant with the potential to sponge around 41 different miRNAs, which target several genes mostly involved in endocytosis, MAP kinase, and PI3K-Akt pathways. Interestingly, circMNTND5 and mecciND1 specifically interact with miRNAs through their unique back-splice junction sequence. These exclusively targeted miRNAs (has-miR-5186, 6888-5p, 8081, 924, 672-5p) are predominantly associated with insulin secretion, proteoglycans in cancer, and MAPK signaling pathways. Moreover, all mt-circRNAs intricately affect the P53 pathway through miRNA sequestration. Remarkably, mc-COX2 and circMNTND5 appear to be involved in the RNA’s biogenesis by antagonizing AGO1/2, EIF4A3, and DGCR8. All mt-circRNAs engaged with IGF2BP proteins crucial in redox signaling, and except mecciND1, they all potentially generate at least one protein resembling the immunoglobulin heavy chain protein. Given P53′s function as a redox-sensitive transcription factor, and insulin’s role as a crucial regulator of energy metabolism, their indirect interplay with mt-circRNAs could influence cellular outcomes. However, due to limited attention and infrequent data availability, it is advisable to conduct more thorough investigations to gain a deeper understanding of the functions of mt-circRNA.</div></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"79 ","pages":"Article 101968"},"PeriodicalIF":3.9,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323312","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}

引用次数: 0

Newer mitochondrial dynamics and their role of calcium signalling in liver regeneration 较新的线粒体动力学及其在肝脏再生中的钙信号作用

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-09-19 DOI: 10.1016/j.mito.2024.101969

Onkar Bedi , Vaibhav Sapra , Manish Kumar , Pawan Krishan

Liver regeneration is a crucial process involved in cellular proliferation, differentiation, and tissue repair. Calcium signaling impact key pathways like hepatocyte growth factor-Met-tyrosine kinase (HGF-Met) transduction pathway, the epidermal growth factor receptor (EGFR) signaling and Ca-mediated nuclear SKHep1 cell proliferation pathway. Intracellular hepatocyte calcium stores are considered as base for the induction of ca-mediated regeneration process. Calcium signaling interplays with HGF, TGF-β, and NF-κB signaling, influence stem cell behavior and triggers MAPK cascade. The mitochondria calcium is impacting on liver rejuvenation by regulating apoptosis and cell division. In conclusion, it is stated that calcium-signaling holds promise for therapeutic liver interventions.

肝脏再生是细胞增殖、分化和组织修复的关键过程。钙信号对肝细胞生长因子-甲胎蛋白-酪氨酸激酶（HGF-Met）转导途径、表皮生长因子受体（EGFR）信号和钙介导的核 SKHep1 细胞增殖途径等关键途径产生影响。肝细胞内的钙储存被认为是诱导钙介导的再生过程的基础。钙信号与 HGF、TGF-β 和 NF-κB 信号相互作用，影响干细胞行为并触发 MAPK 级联。线粒体钙通过调节细胞凋亡和细胞分裂影响肝脏再生。总之，钙信号有望用于肝脏干预治疗。

引用次数: 0

Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line 克雷布斯循环衍生物、富马酸二甲酯和伊他康酸能控制炎性人类小胶质细胞系的代谢重编程

IF 3.9 3区生物学 Q2 CELL BIOLOGY

Mitochondrion

Pub Date : 2024-09-12 DOI: 10.1016/j.mito.2024.101966

Moris Sangineto , Martina Ciarnelli , Archana Moola , Vidyasagar Naik Bukke , Tommaso Cassano , Rosanna Villani , Antonino D. Romano , Giuseppe Di Gioia , Carlo Avolio , Gaetano Serviddio

Metabolic reprogramming drives inflammatory activity in macrophages, including microglia, with Krebs cycle (KC) intermediates playing a crucial role as signaling molecules. Here, we show that the bioenergetic profile of LPS-activated human microglial clone 3 cell line (HMC3) is characterized by high levels of glycolysis and mitochondrial (mt) respiration, and the treatment with KC derivatives, namely dimethyl-fumarate (DMF) and itaconate (ITA), almost restores normal metabolism. However, despite comparable bioenergetic and anti-inflammatory effects, the mt hyper-activity was differentially modulated by DMF and ITA. DMF normalized complex I activity, while ITA dampened both complex I and II hyper-activity counteracting oxidative stress more efficiently.

代谢重编程驱动着包括小胶质细胞在内的巨噬细胞的炎症活动，其中克雷布斯循环（KC）中间产物作为信号分子发挥着至关重要的作用。在这里，我们发现 LPS 激活的人小胶质细胞克隆 3 细胞系（HMC3）的生物能特征是高水平的糖酵解和线粒体（mt）呼吸，而用 KC 衍生物（即富马酸二甲酯（DMF）和伊他康酸（ITA））处理几乎可以恢复正常代谢。然而，尽管生物能和抗炎效果相当，但 DMF 和 ITA 对 mt 的高活性有不同的调节作用。DMF 使复合体 I 的活性恢复正常，而 ITA 则抑制了复合体 I 和 II 的高活性，从而更有效地对抗氧化应激。

{"title":"Krebs cycle derivatives, dimethyl fumarate and itaconate, control metabolic reprogramming in inflammatory human microglia cell line","authors":"Moris Sangineto , Martina Ciarnelli , Archana Moola , Vidyasagar Naik Bukke , Tommaso Cassano , Rosanna Villani , Antonino D. Romano , Giuseppe Di Gioia , Carlo Avolio , Gaetano Serviddio","doi":"10.1016/j.mito.2024.101966","DOIUrl":"10.1016/j.mito.2024.101966","url":null,"abstract":"<div><p>Metabolic reprogramming drives inflammatory activity in macrophages, including microglia, with Krebs cycle (KC) intermediates playing a crucial role as signaling molecules. Here, we show that the bioenergetic profile of LPS-activated human microglialclone 3 cell line (HMC3) is characterized by high levels of glycolysis and mitochondrial (mt) respiration, and the treatment with KC derivatives, namely dimethyl-fumarate (DMF) and itaconate (ITA), almost restores normal metabolism. However, despite comparable bioenergetic and anti-inflammatory effects, the mt hyper-activity was differentially modulated by DMF and ITA. DMF normalized complex I activity, while ITA dampened both complex I and II hyper-activity counteracting oxidative stress more efficiently.</p></div>","PeriodicalId":18606,"journal":{"name":"Mitochondrion","volume":"79 ","pages":"Article 101966"},"PeriodicalIF":3.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1567724924001247/pdfft?md5=6a5becc343b5697d574ecae4cead3197&pid=1-s2.0-S1567724924001247-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142271380","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}

引用次数: 0