-
Biochemistry. Biokhimiia Oct 2016Mitochondrial DNA (mtDNA) in cells is organized in nucleoids containing DNA and various proteins. This review discusses questions of organization and structural dynamics... (Review)
Review
Mitochondrial DNA (mtDNA) in cells is organized in nucleoids containing DNA and various proteins. This review discusses questions of organization and structural dynamics of nucleoids as well as their protein components. The structures of mt-nucleoid from different organisms are compared. The currently accepted model of nucleoid organization is described and questions needing answers for better understanding of the fine mechanisms of the mitochondrial genetic apparatus functioning are discussed.
Topics: Animals; DNA, Mitochondrial; Genome, Mitochondrial; Humans; Mitochondria; Mitochondrial Proteins
PubMed: 27908231
DOI: 10.1134/S0006297916100047 -
Biochimica Et Biophysica Acta Nov 2015Mitochondrial DNA has long been posited as a likely target of oxidative damage induced mutation during the ageing process. Research over the past decades has uncovered... (Review)
Review
Mitochondrial DNA has long been posited as a likely target of oxidative damage induced mutation during the ageing process. Research over the past decades has uncovered the accumulation of mitochondrial DNA mutations in association with a mosaic pattern of cells displaying mitochondrial dysfunction in ageing individuals. Unfortunately, the underlying mechanisms are far less straightforward than originally anticipated. Recent research on mitochondria reveals that these genomes are far less helpless than originally envisioned. Additionally, new technologies have allowed us to analyze the mutational signatures of many more somatic mitochondrial DNA mutations, revealing surprising patterns that are inconsistent with a DNA-oxidative damage based hypothesis. In this review, we will discuss these recent observations and new insights into the eccentricities of mitochondrial genetics, and their impact on our understanding of mitochondrial mutations and their role in the ageing process. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.
Topics: Animals; DNA Damage; DNA Replication; DNA, Mitochondrial; Free Radicals; Humans; Mutation
PubMed: 26050972
DOI: 10.1016/j.bbabio.2015.06.001 -
Molecular Cell Mar 2016Mitochondria perform diverse yet interconnected cellular functions and are dynamically regulated by complex signaling pathways. Interest in this fascinating organelle...
Mitochondria perform diverse yet interconnected cellular functions and are dynamically regulated by complex signaling pathways. Interest in this fascinating organelle has recently undergone a renaissance due to a series of discoveries revealing that mitochondrial function goes beyond the generation of molecular fuel. This Timeline highlights some of the groundbreaking events over the last 30 years in our understanding of how mitochondria are made and turned over, and how they integrate and signal within the cell and organism. To view this Timeline, open or download the PDF.
Topics: Animals; Apoptosis; Biomedical Research; Cell Biology; Cellular Senescence; DNA, Mitochondrial; Energy Metabolism; History, 20th Century; History, 21st Century; Humans; Mitochondria; Mutation
PubMed: 26942681
DOI: 10.1016/j.molcel.2016.02.015 -
Experimental & Molecular Medicine May 2023Mitochondria are of fundamental importance in programmed cell death, cellular metabolism, and intracellular calcium concentration modulation, and inheritable... (Review)
Review
Mitochondria are of fundamental importance in programmed cell death, cellular metabolism, and intracellular calcium concentration modulation, and inheritable mitochondrial disorders via mitochondrial DNA (mtDNA) mutation cause several diseases in various organs and systems. Nevertheless, mtDNA editing, which plays an essential role in the treatment of mitochondrial disorders, still faces several challenges. Recently, programmable editing tools for mtDNA base editing, such as cytosine base editors derived from DddA (DdCBEs), transcription activator-like effector (TALE)-linked deaminase (TALED), and zinc finger deaminase (ZFD), have emerged with considerable potential for correcting pathogenic mtDNA variants. In this review, we depict recent advances in the field, including structural biology and repair mechanisms, and discuss the prospects of using base editing tools on mtDNA to broaden insight into their medical applicability for treating mitochondrial diseases.
Topics: Humans; Gene Editing; Genome, Mitochondrial; Mitochondria; DNA, Mitochondrial; Mitochondrial Diseases
PubMed: 37121968
DOI: 10.1038/s12276-023-00973-7 -
Biochimica Et Biophysica Acta. Gene... Mar 2019Correct expression of the mitochondrially-encoded genes is critical for the production of the components of the oxidative phosphorylation machinery. Post-transcriptional... (Review)
Review
Correct expression of the mitochondrially-encoded genes is critical for the production of the components of the oxidative phosphorylation machinery. Post-transcriptional modifications of mitochondrial transcripts have been emerging as an important regulatory feature of mitochondrial gene expression. Here we review the current knowledge on how the mammalian mitochondrial epitranscriptome participates in regulating mitochondrial homeostasis. In particular, we focus on the latest breakthroughs made towards understanding the roles of the modified nucleotides in mitochondrially-encoded ribosomal and transfer RNAs, the enzymes responsible for introducing these modifications and on recent transcriptome-wide studies reporting modifications to mitochondrial messenger RNAs. This article is part of a Special Issue entitled: mRNA modifications in gene expression control edited by Dr. Matthias Soller and Dr. Rupert Fray.
Topics: Animals; DNA, Mitochondrial; Epigenesis, Genetic; Humans; RNA Processing, Post-Transcriptional; Transcriptome
PubMed: 30529456
DOI: 10.1016/j.bbagrm.2018.11.005 -
International Journal of Molecular... Jan 2023Atherosclerosis is a multifactorial inflammatory pathology that involves metabolic processes. Improvements in therapy have drastically reduced the prognosis of... (Review)
Review
Atherosclerosis is a multifactorial inflammatory pathology that involves metabolic processes. Improvements in therapy have drastically reduced the prognosis of cardiovascular disease. Nevertheless, a significant residual risk is still relevant, and is related to unmet therapeutic targets. Endothelial dysfunction and lipid infiltration are the primary causes of atherosclerotic plaque progression. In this contest, mitochondrial dysfunction can affect arterial wall cells, in particular macrophages, smooth muscle cells, lymphocytes, and endothelial cells, causing an increase in reactive oxygen species (ROS), leading to oxidative stress, chronic inflammation, and intracellular lipid deposition. The detection and characterization of mitochondrial DNA (mtDNA) is crucial for assessing mitochondrial defects and should be considered the goal for new future therapeutic interventions. In this review, we will focus on a new idea, based on the analysis of data from many research groups, namely the link between mitochondrial impairment and endothelial dysfunction and, in particular, its effect on atherosclerosis and aging. Therefore, we discuss known and novel mitochondria-targeting therapies in the contest of atherosclerosis.
Topics: Humans; Endothelial Cells; Atherosclerosis; Plaque, Atherosclerotic; Mitochondria; Oxidative Stress; Reactive Oxygen Species; DNA, Mitochondrial; Lipids
PubMed: 36674602
DOI: 10.3390/ijms24021086 -
International Journal of Molecular... Sep 2022Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that... (Review)
Review
Mitochondria are the only organelles, along with the nucleus, that have their own DNA. Mitochondrial DNA (mtDNA) is a double-stranded circular molecule of ~16.5 kbp that can exist in multiple copies within the organelle. Both strands are translated and encode for 22 tRNAs, 2 rRNAs, and 13 proteins. mtDNA molecules are anchored to the inner mitochondrial membrane and, in association with proteins, form a structure called nucleoid, which exerts a structural and protective function. Indeed, mitochondria have evolved mechanisms necessary to protect their DNA from chemical and physical lesions such as DNA repair pathways similar to those present in the nucleus. However, there are mitochondria-specific mechanisms such as rapid mtDNA turnover, fission, fusion, and mitophagy. Nevertheless, mtDNA mutations may be abundant in somatic tissue due mainly to the proximity of the mtDNA to the oxidative phosphorylation (OXPHOS) system and, consequently, to the reactive oxygen species (ROS) formed during ATP production. In this review, we summarise the most common types of mtDNA lesions and mitochondria repair mechanisms. The second part of the review focuses on the physiological role of mtDNA damage in ageing and the effect of mtDNA mutations in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Considering the central role of mitochondria in maintaining cellular homeostasis, the analysis of mitochondrial function is a central point for developing personalised medicine.
Topics: Adenosine Triphosphate; DNA Damage; DNA Repair; DNA, Mitochondrial; Humans; Mitochondrial Diseases; Neurodegenerative Diseases; Reactive Oxygen Species
PubMed: 36232693
DOI: 10.3390/ijms231911391 -
Journal of Translational Medicine May 2023Recent evidence has shown significant roles of mitochondria-derived vesicles (MDVs) in mitochondrial quality control (MQC) system. Under mild stress condition, MDVs are... (Review)
Review
Recent evidence has shown significant roles of mitochondria-derived vesicles (MDVs) in mitochondrial quality control (MQC) system. Under mild stress condition, MDVs are formed to carry the malfunctioned mitochondrial components, such as mitochondrial DNA (mtDNA), peptides, proteins and lipids, to be eliminated to restore normal mitochondrial structure and functions. Under severe oxidative stress condition, mitochondrial dynamics (fission/fusion) and mitophagy are predominantly activated to rescue mitochondrial structure and functions. Additionally, MDVs generation can be also triggered as the major MQC machinery to cope with unhealthy mitochondria when mitophagy is unsuccessful for eliminating the damaged mitochondria or mitochondrial fission/fusion fail to recover the mitochondrial structure and functions. This review summarizes the current knowledge on MDVs and discuss their roles in physiologic and pathophysiologic conditions. In addition, the potential clinical relevance of MDVs in therapeutics and diagnostics of kidney stone disease (KSD) are emphasized.
Topics: Humans; Mitochondria; Oxidative Stress; DNA, Mitochondrial; Mitophagy; Kidney Calculi
PubMed: 37131163
DOI: 10.1186/s12967-023-04133-3 -
Trends in Cell Biology Apr 2021Mammalian cells, with the exception of erythrocytes, harbor mitochondria, which are organelles that provide energy, intermediate metabolites, and additional activities... (Review)
Review
Mammalian cells, with the exception of erythrocytes, harbor mitochondria, which are organelles that provide energy, intermediate metabolites, and additional activities to sustain cell viability, replication, and function. Mitochondria contain multiple copies of a circular genome called mitochondrial DNA (mtDNA), whose individual sequences are rarely identical (homoplasmy) because of inherited or sporadic mutations that result in multiple mtDNA genotypes (heteroplasmy). Here, we examine potential mechanisms for maintenance or shifts in heteroplasmy that occur in induced pluripotent stem cells (iPSCs) generated by cellular reprogramming, and further discuss manipulations that can alter heteroplasmy to impact stem and differentiated cell performance. This additional insight will assist in developing more robust iPSC-based models of disease and differentiated cell therapies.
Topics: Animals; Cellular Reprogramming; DNA, Mitochondrial; Induced Pluripotent Stem Cells; Mitochondria; Mitochondrial Dynamics
PubMed: 33422359
DOI: 10.1016/j.tcb.2020.12.009 -
Cells Feb 2022Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of... (Review)
Review
Mitochondria are primarily involved in cell bioenergetics, regulation of redox homeostasis, and cell death/survival signaling. An immunostimulatory property of mitochondria has also been recognized which is deployed through the extracellular release of entire or portioned organelle and/or mitochondrial DNA (mtDNA) unloading. Dynamic homo- and heterotypic interactions involving mitochondria have been described. Each type of connection has functional implications that eventually optimize mitochondrial activity according to the bioenergetic demands of a specific cell/tissue. Inter-organelle communications may also serve as molecular platforms for the extracellular release of mitochondrial components and subsequent ignition of systemic inflammation. Age-related chronic inflammation (inflamm-aging) has been associated with mitochondrial dysfunction and increased extracellular release of mitochondrial components-in particular, cell-free mtDNA. The close relationship between mitochondrial dysfunction and cellular senescence further supports the central role of mitochondria in the aging process and its related conditions. Here, we provide an overview of (1) the mitochondrial genetic system and the potential routes for generating and releasing mtDNA intermediates; (2) the pro-inflammatory pathways elicited by circulating mtDNA; (3) the participation of inter-organelle contacts to mtDNA homeostasis; and (4) the link of these processes with senescence and age-associated conditions.
Topics: DNA, Mitochondrial; Humans; Inflammation; Mitochondria; Mitochondrial Membranes
PubMed: 35203322
DOI: 10.3390/cells11040675