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Central dogma rates in human mitochondria. 人类线粒体中的中心教条率。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae036
Erik McShane, L Stirling Churchman
{"title":"Central dogma rates in human mitochondria.","authors":"Erik McShane, L Stirling Churchman","doi":"10.1093/hmg/ddae036","DOIUrl":"10.1093/hmg/ddae036","url":null,"abstract":"<p><p>In human cells, the nuclear and mitochondrial genomes engage in a complex interplay to produce dual-encoded oxidative phosphorylation (OXPHOS) complexes. The coordination of these dynamic gene expression processes is essential for producing matched amounts of OXPHOS protein subunits. This review focuses on our current understanding of the mitochondrial central dogma rates, highlighting the striking differences in gene expression rates between mitochondrial and nuclear genes. We synthesize a coherent model of mitochondrial gene expression kinetics, highlighting the emerging principles and emphasizing where more precise measurements would be beneficial. Such an understanding is pivotal for grasping the unique aspects of mitochondrial function and its role in cellular energetics, and it has profound implications for aging, metabolic disorders, and neurodegenerative diseases.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Mitochondrial DNA release and sensing in innate immune responses. 先天性免疫反应中的线粒体 DNA 释放和感应。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae031
Jordyn J VanPortfliet, Cole Chute, Yuanjiu Lei, Timothy E Shutt, A Phillip West
{"title":"Mitochondrial DNA release and sensing in innate immune responses.","authors":"Jordyn J VanPortfliet, Cole Chute, Yuanjiu Lei, Timothy E Shutt, A Phillip West","doi":"10.1093/hmg/ddae031","DOIUrl":"10.1093/hmg/ddae031","url":null,"abstract":"<p><p>Mitochondria are pleiotropic organelles central to an array of cellular pathways including metabolism, signal transduction, and programmed cell death. Mitochondria are also key drivers of mammalian immune responses, functioning as scaffolds for innate immune signaling, governing metabolic switches required for immune cell activation, and releasing agonists that promote inflammation. Mitochondrial DNA (mtDNA) is a potent immunostimulatory agonist, triggering pro-inflammatory and type I interferon responses in a host of mammalian cell types. Here we review recent advances in how mtDNA is detected by nucleic acid sensors of the innate immune system upon release into the cytoplasm and extracellular space. We also discuss how the interplay between mtDNA release and sensing impacts cellular innate immune endpoints relevant to health and disease.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Illuminating mitochondrial translation through mouse models. 通过小鼠模型阐明线粒体翻译。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae020
Laetitia A Hughes, Oliver Rackham, Aleksandra Filipovska
{"title":"Illuminating mitochondrial translation through mouse models.","authors":"Laetitia A Hughes, Oliver Rackham, Aleksandra Filipovska","doi":"10.1093/hmg/ddae020","DOIUrl":"10.1093/hmg/ddae020","url":null,"abstract":"<p><p>Mitochondria are hubs of metabolic activity with a major role in ATP conversion by oxidative phosphorylation (OXPHOS). The mammalian mitochondrial genome encodes 11 mRNAs encoding 13 OXPHOS proteins along with 2 rRNAs and 22 tRNAs, that facilitate their translation on mitoribosomes. Maintaining the internal production of core OXPHOS subunits requires modulation of the mitochondrial capacity to match the cellular requirements and correct insertion of particularly hydrophobic proteins into the inner mitochondrial membrane. The mitochondrial translation system is essential for energy production and defects result in severe, phenotypically diverse diseases, including mitochondrial diseases that typically affect postmitotic tissues with high metabolic demands. Understanding the complex mechanisms that underlie the pathologies of diseases involving impaired mitochondrial translation is key to tailoring specific treatments and effectively targeting the affected organs. Disease mutations have provided a fundamental, yet limited, understanding of mitochondrial protein synthesis, since effective modification of the mitochondrial genome has proven challenging. However, advances in next generation sequencing, cryoelectron microscopy, and multi-omic technologies have revealed unexpected and unusual features of the mitochondrial protein synthesis machinery in the last decade. Genome editing tools have generated unique models that have accelerated our mechanistic understanding of mitochondrial translation and its physiological importance. Here we review the most recent mouse models of disease pathogenesis caused by defects in mitochondrial protein synthesis and discuss their value for preclinical research and therapeutic development.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Tools for editing the mammalian mitochondrial genome. 编辑哺乳动物线粒体基因组的工具。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae037
Carlos T Moraes
{"title":"Tools for editing the mammalian mitochondrial genome.","authors":"Carlos T Moraes","doi":"10.1093/hmg/ddae037","DOIUrl":"10.1093/hmg/ddae037","url":null,"abstract":"<p><p>The manipulation of animal mitochondrial genomes has long been a challenge due to the lack of an effective transformation method. With the discovery of specific gene editing enzymes, designed to target pathogenic mitochondrial DNA mutations (often heteroplasmic), the selective removal or modification of mutant variants has become a reality. Because mitochondria cannot efficiently import RNAs, CRISPR has not been the first choice for editing mitochondrial genes. However, the last few years witnessed an explosion in novel and optimized non-CRISPR approaches to promote double-strand breaks or base-edit of mtDNA in vivo. Engineered forms of specific nucleases and cytidine/adenine deaminases form the basis for these techniques. I will review the newest developments that constitute the current toolbox for animal mtDNA gene editing in vivo, bringing these approaches not only to the exploration of mitochondrial function, but also closer to clinical use.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
RNA degradation in human mitochondria: the journey is not finished. 人类线粒体中的 RNA 降解：旅程尚未结束。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae043
Giulia Santonoceto, Aneta Jurkiewicz, Roman J Szczesny
{"title":"RNA degradation in human mitochondria: the journey is not finished.","authors":"Giulia Santonoceto, Aneta Jurkiewicz, Roman J Szczesny","doi":"10.1093/hmg/ddae043","DOIUrl":"10.1093/hmg/ddae043","url":null,"abstract":"<p><p>Mitochondria are vital organelles present in almost all eukaryotic cells. Although most of the mitochondrial proteins are nuclear-encoded, mitochondria contain their own genome, whose proper expression is necessary for mitochondrial function. Transcription of the human mitochondrial genome results in the synthesis of long polycistronic transcripts that are subsequently processed by endonucleases to release individual RNA molecules, including precursors of sense protein-encoding mRNA (mt-mRNA) and a vast amount of antisense noncoding RNAs. Because of mitochondrial DNA (mtDNA) organization, the regulation of individual gene expression at the transcriptional level is limited. Although transcription of most protein-coding mitochondrial genes occurs with the same frequency, steady-state levels of mature transcripts are different. Therefore, post-transcriptional processes are important for regulating mt-mRNA levels. The mitochondrial degradosome is a complex composed of the RNA helicase SUV3 (also known as SUPV3L1) and polynucleotide phosphorylase (PNPase, PNPT1). It is the best-characterized RNA-degrading machinery in human mitochondria, which is primarily responsible for the decay of mitochondrial antisense RNA. The mechanism of mitochondrial sense RNA decay is less understood. This review aims to provide a general picture of mitochondrial genome expression, with a particular focus on mitochondrial RNA (mtRNA) degradation.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
The molecular machinery for maturation of primary mtDNA transcripts. 初级 mtDNA 转录本成熟的分子机制。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae023
Ana Vučković, Christoph Freyer, Anna Wredenberg, Hauke S Hillen
{"title":"The molecular machinery for maturation of primary mtDNA transcripts.","authors":"Ana Vučković, Christoph Freyer, Anna Wredenberg, Hauke S Hillen","doi":"10.1093/hmg/ddae023","DOIUrl":"10.1093/hmg/ddae023","url":null,"abstract":"<p><p>Human mitochondria harbour a circular, polyploid genome (mtDNA) encoding 11 messenger RNAs (mRNAs), two ribosomal RNAs (rRNAs) and 22 transfer RNAs (tRNAs). Mitochondrial transcription produces long, polycistronic transcripts that span almost the entire length of the genome, and hence contain all three types of RNAs. The primary transcripts then undergo a number of processing and maturation steps, which constitute key regulatory points of mitochondrial gene expression. The first step of mitochondrial RNA processing consists of the separation of primary transcripts into individual, functional RNA molecules and can occur by two distinct pathways. Both are carried out by dedicated molecular machineries that substantially differ from RNA processing enzymes found elsewhere. As a result, the underlying molecular mechanisms remain poorly understood. Over the last years, genetic, biochemical and structural studies have identified key players involved in both RNA processing pathways and provided the first insights into the underlying mechanisms. Here, we review our current understanding of RNA processing in mammalian mitochondria and provide an outlook on open questions in the field.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Mitochondrial protein synthesis quality control. 线粒体蛋白质合成质量控制。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae012
Lidiia Koludarova, Brendan J Battersby
{"title":"Mitochondrial protein synthesis quality control.","authors":"Lidiia Koludarova, Brendan J Battersby","doi":"10.1093/hmg/ddae012","DOIUrl":"10.1093/hmg/ddae012","url":null,"abstract":"<p><p>Human mitochondrial DNA is one of the most simplified cellular genomes and facilitates compartmentalized gene expression. Within the organelle, there is no physical barrier to separate transcription and translation, nor is there evidence that quality control surveillance pathways are active to prevent translation on faulty mRNA transcripts. Mitochondrial ribosomes synthesize 13 hydrophobic proteins that require co-translational insertion into the inner membrane of the organelle. To maintain the integrity of the inner membrane, which is essential for organelle function, requires responsive quality control mechanisms to recognize aberrations in protein synthesis. In this review, we explore how defects in mitochondrial protein synthesis can arise due to the culmination of inherent mistakes that occur throughout the steps of gene expression. In turn, we examine the stepwise series of quality control processes that are needed to eliminate any mistakes that would perturb organelle homeostasis. We aim to provide an integrated view on the quality control mechanisms of mitochondrial protein synthesis and to identify promising avenues for future research.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139570087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Coordinating mitochondrial translation with assembly of the OXPHOS complexes. 协调线粒体翻译与 OXPHOS 复合物的组装。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae025
Laura S Kremer, Peter Rehling
{"title":"Coordinating mitochondrial translation with assembly of the OXPHOS complexes.","authors":"Laura S Kremer, Peter Rehling","doi":"10.1093/hmg/ddae025","DOIUrl":"10.1093/hmg/ddae025","url":null,"abstract":"<p><p>The mitochondrial oxidative phosphorylation (OXPHOS) system produces the majority of energy required by cells. Given the mitochondrion's endosymbiotic origin, the OXPHOS machinery is still under dual genetic control where most OXPHOS subunits are encoded by the nuclear DNA and imported into mitochondria, while a small subset is encoded on the mitochondrion's own genome, the mitochondrial DNA (mtDNA). The nuclear and mtDNA encoded subunits must be expressed and assembled in a highly orchestrated fashion to form a functional OXPHOS system and meanwhile prevent the generation of any harmful assembly intermediates. While several mechanisms have evolved in eukaryotes to achieve such a coordinated expression, this review will focus on how the translation of mtDNA encoded OXPHOS subunits is tailored to OXPHOS assembly.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Decoding the Enigma: Translation Termination in Human Mitochondria. 解码之谜：人类线粒体中的翻译终止。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae032
Annika Krüger, Daria Kovalchuk, Dmitrii Shiriaev, Joanna Rorbach
{"title":"Decoding the Enigma: Translation Termination in Human Mitochondria.","authors":"Annika Krüger, Daria Kovalchuk, Dmitrii Shiriaev, Joanna Rorbach","doi":"10.1093/hmg/ddae032","DOIUrl":"10.1093/hmg/ddae032","url":null,"abstract":"<p><p>Mitochondrial translation is a complex process responsible for the synthesis of essential proteins involved in oxidative phosphorylation, a fundamental pathway for cellular energy production. Central to this process is the termination phase, where dedicated factors play a pivotal role in ensuring accurate and timely protein production. This review provides a comprehensive overview of the current understanding of translation termination in human mitochondria, emphasizing structural features and molecular functions of two mitochondrial termination factors mtRF1 and mtRF1a.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Mitochondrial molecular genetics and human disease. 线粒体分子遗传学与人类疾病。
IF 3.1 2区 生物学
Human molecular genetics Pub Date : 2024-05-22 DOI: 10.1093/hmg/ddae049
Eric A Shoubridge, Antoni Barrientos
{"title":"Mitochondrial molecular genetics and human disease.","authors":"Eric A Shoubridge, Antoni Barrientos","doi":"10.1093/hmg/ddae049","DOIUrl":"10.1093/hmg/ddae049","url":null,"abstract":"","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141081212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
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