重新审视核线粒体DNA转移:从基因组噪音到衰老的标志

IF 12.4 1区 医学 Q1 CELL BIOLOGY
Emanuele Marzetti , Rosa Di Lorenzo , Riccardo Calvani , Helio José Coelho-Junior , Vito Pesce , Francesco Landi , Christiaan Leeuwenburgh , Anna Picca
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引用次数: 0

摘要

线粒体DNA (mtDNA)片段的核插入(NUMTs)是一种进化上保守的现象,起源于线粒体与宿主细胞之间古老的内共生关系。这些插入主要定位于基因间区或调控区附近,并且通常在具有高代谢活性的组织中富集。numt曾经被认为是惰性的假基因或基因组伪产物,现在被认为是能够调节核结构和细胞功能的动态元素。全基因组测序的进展揭示了numt在物种间的显著多样性,包括人类的多态变异,这表明numt正在发生。应力诱导的线粒体损伤促进mtDNA释放和随后通过非同源末端连接的核整合,这一机制可能在衰老组织中加剧。研究表明,numt可能与衰老的一些生物学特征相交。最近,NUMT在大脑中的积累被证明与认知能力下降和寿命缩短有关,这意味着NUMT与生物衰老和相关疾病有关。此外,在致癌基因座中也观察到numt,提示其在致癌过程中具有潜在的作用。这篇综述综合了目前支持NUMT产生的分子机制的证据,并探讨了它们与衰老生物学的交叉。我们研究numt如何影响线粒体-核通讯,促进炎症,影响端粒动力学和细胞衰老。我们还强调了理解numt在生命阶段和疾病状态中的生物学影响的相关性,从而为新的生物标志物和治疗策略提供信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Nuclear mitochondrial DNA transfer revisited: From genomic noise to hallmark of aging
Nuclear insertions of mitochondrial DNA (mtDNA) segments (NUMTs) represent an evolutionarily conserved phenomenon originating from the ancient endosymbiotic relationship between mitochondria and host cells. These insertions predominantly localize near intergenic or regulatory regions and are often enriched in tissues with high metabolic activity. Once regarded as inert pseudogenes or genomic artifacts, NUMTs are now recognized as dynamic elements capable of modulating nuclear architecture and cellular function. Advances in whole-genome sequencing have revealed a remarkable diversity of NUMTs across species, including polymorphic variants in humans that suggest ongoing NUMTogenesis. Stress-induced mitochondrial damage promotes mtDNA release and subsequent nuclear integration via non-homologous end joining, a mechanism that may be exacerbated in aging tissues. Studies suggest that NUMTs may intersect with some biological hallmarks of aging. Recently, NUMT accumulation in the brain was shown to correlate with cognitive decline and reduced lifespan, implicating NUMTs in biological aging and associated conditions. Additionally, NUMTs have been observed in oncogenic loci, suggesting potential roles in carcinogenesis. This review synthesizes current evidence on the molecular mechanisms underpinning NUMT generation and explores their intersection with aging biology. We examine how NUMTs may influence mitochondrial−nuclear communication, promote inflammation, and affect telomere dynamics and cellular senescence. We also highlight the relevance of understanding the biological impact of NUMTs across life stages and disease states to inform novel biomarkers and therapeutic strategies.
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来源期刊
Ageing Research Reviews
Ageing Research Reviews 医学-老年医学
CiteScore
19.80
自引率
2.30%
发文量
216
审稿时长
55 days
期刊介绍: With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.
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