bims-midmar Biomed News
on Mitochondrial DNA maintenance and replication
Issue of 2021–10–31
eleven papers selected by
Flavia Söllner, Ludwig-Maximilians University
  1. Mitoepigenetics: An intriguing regulatory layer in aging and metabolic-related diseases.
  2. Phase separation drives the self-assembly of mitochondrial nucleoids for transcriptional modulation.
  3. Quantitative Analysis of RNA Editing at Specific Sites in Plant Mitochondria or Chloroplasts Using DNA Sequencing.
  4. It takes two to tango; the essential role of ER-mitochondrial contact sites in mitochondrial dynamics.
  5. Understanding viral replication and transcription using single-molecule techniques.
  6. The many roles mitochondria play in mammalian aging.
  7. Functional Analyses of Mitoribosome 54S Subunit Devoid of Mitochondria-Specific Protein Sequences.
  8. Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures.
  9. Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain.
  10. Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2.
  11. Antisense Oligonucleotide-Mediated Silencing of Mitochondrial Fusion and Fission Factors Modulates Mitochondrial Dynamics and Rescues Mitochondrial Dysfunction.
  1. Free Radic Biol Med. 2021 Oct 26. pii: S0891-5849(21)00781-4. [Epub ahead of print]
    Mitoepigenetics: An intriguing regulatory layer in aging and metabolic-related diseases.
    Ke Cao, Zhihui Feng, Feng Gao, Weijin Zang, Jiankang Liu.
      As a key organelle in eukaryotic cells, mitochondria play a central role in maintaining normal cellular functions. Mitochondrial dysfunction is reported to be closely related with aging and various diseases. Epigenetic modifications in nuclear genome provide a substantial layer for the modulation of nuclear-encoded gene expression. However, whether mitochondria could also be subjected to such similar epigenetic alterations and the involved mechanisms remain largely obscure and controversial. Recently, accumulating evidence has suggested that mitochondrial epigenetics, also known as mitoepigenetics may serve as an intriguing regulatory layer in mitochondrial DNA (mtDNA)-encoded gene expression. Given the potential regulatory role of mitoepigenetics, mitochondrial dysfunction derived from mitoepigenetics-induced abnormal gene expression could also be closely associated with aging and disease development. In this review, we summarized the recent advances in mitoepigenetics, with a special focus on mtDNA methylation in aging and metabolic-related diseases as well as the new methods and technologies for the study of mitoepigenetics. Uncovering the regulatory role of mitoepigenetics will help to understand the underlying mechanisms of mitochondrial dysfunction and provide novel strategies for delaying aging and preventing metabolic-related diseases.
    Keywords:  Mitochondrial DNA (mtDNA) methylation; Mitochondrial epigenetics (mitoepigenetics); Mitochondrial non-coding RNAs (ncRNAs); Post-translational modifications (PTMs); mtDNA-associated proteins
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.10.031
  2. Nat Struct Mol Biol. 2021 Oct 28.
    Phase separation drives the self-assembly of mitochondrial nucleoids for transcriptional modulation.
    Qi Long, Yanshuang Zhou, Hao Wu, Shiwei Du, Mingli Hu, Juntao Qi, Wei Li, Jingyi Guo, Yi Wu, Liang Yang, Ge Xiang, Liang Wang, Shouhua Ye, Jiayuan Wen, Heng Mao, Junwei Wang, Hui Zhao, Wai-Yee Chan, Jinsong Liu, Yonglong Chen, Pilong Li, Xingguo Liu.
      Mitochondria, the only semiautonomous organelles in mammalian cells, possess a circular, double-stranded genome termed mitochondrial DNA (mtDNA). While nuclear genomic DNA compaction, chromatin compartmentalization and transcription are known to be regulated by phase separation, how the mitochondrial nucleoid, a highly compacted spherical suborganelle, is assembled and functions is unknown. Here we assembled mitochondrial nucleoids in vitro and show that mitochondrial transcription factor A (TFAM) undergoes phase separation with mtDNA to drive nucleoid self-assembly. Moreover, nucleoid droplet formation promotes recruitment of the transcription machinery via a special, co-phase separation that concentrates transcription initiation, elongation and termination factors, and retains substrates to facilitate mtDNA transcription. We propose a model of mitochondrial nucleoid self-assembly driven by phase separation, and a pattern of co-phase separation involved in mitochondrial transcriptional regulation, which orchestrates the roles of TFAM in both mitochondrial nucleoid organization and transcription.
    DOI:  https://doi.org/10.1038/s41594-021-00671-w
  3. Bio Protoc. 2021 Sep 20. 11(18): e4154
    Quantitative Analysis of RNA Editing at Specific Sites in Plant Mitochondria or Chloroplasts Using DNA Sequencing.
    Yang Yang, Weixing Shan.
      Cytidine-to-uridine (C-to-U) RNA editing is one of the most important post-transcriptional RNA processing in plant mitochondria and chloroplasts. Several techniques have been developed to detect the RNA editing efficiency in plant mitochondria and chloroplasts, such as poisoned primer extension (PPE) assays, high-resolution melting (HRM) analysis, and DNA sequencing. Here, we describe a method for the quantitative detection of RNA editing at specific sites by sequencing cDNA from plant leaves to further evaluate the effect of different treatments or plant mutants on the C to U RNA editing in mitochondria and chloroplasts.
    Keywords:  C to U RNA editing; Chloroplasts; DNA sequencing; Editing extent; Mitochondria
    DOI:  https://doi.org/10.21769/BioProtoc.4154
  4. Int J Biochem Cell Biol. 2021 Oct 22. pii: S1357-2725(21)00182-5. [Epub ahead of print] 106101
    It takes two to tango; the essential role of ER-mitochondrial contact sites in mitochondrial dynamics.
    Irene M G M Hemel, Rita Sarantidou, Mike Gerards.
      Mitochondria change their shape, size and number, in response to cellular demand, through mitochondrial dynamics. The interaction between mitochondria and the ER, through ER-mitochondrial contact sites, is crucial in mitochondrial dynamics. Several protein complexes tethering mitochondria to the ER include proteins involved in fission or fusion but also proteins involved in calcium homeostasis, which is known to affect mitochondrial dynamics. The formation of these contact sites are especially important for mitochondrial fission as these contact sites induce both outer and inner membrane constriction, prior to recruitment of Drp1. While the exact molecular mechanisms behind these constrictions remain uncertain, several hypotheses have been proposed. In this review, we discuss the involvement of tethering complexes in mitochondrial dynamics and provide an overview of the current knowledge and hypotheses on the constriction of the outer and inner mitochondrial membrane at ER-mitochondrial contact sites.
    Keywords:  ER-mitochondrial contact; Mitochondrial dynamics; Mitochondrial membrane constriction
    DOI:  https://doi.org/10.1016/j.biocel.2021.106101
  5. Enzymes. 2021 ;pii: S1874-6047(21)00015-9. [Epub ahead of print]49 83-113
    Understanding viral replication and transcription using single-molecule techniques.
    Emmanuelle Pitre, Aartjan J W Te Velthuis.
      DNA and RNA viruses depend on one or more enzymes to copy and transcribe their genome, such as a polymerase, helicase, or exonuclease. Because of the important role of these enzymes in the virus replication cycle, they are key targets for antiviral development. To better understand the function of these enzymes and their interactions with host and viral factors, biochemical, structural and single-molecule approaches have been used to study them. Each of these techniques has its own strengths, and single-molecule methods have proved particularly powerful in providing insight into the step-sizes of motor proteins, heterogeneity of enzymatic activities, transient conformational changes, and force-sensitivity of reactions. Here we will discuss how single-molecule FRET, magnetic tweezers, optical tweezers, atomic force microscopy and flow stretching approaches have revealed novel insights into polymerase fidelity, the mechanism of action of antivirals, and the protein choreography within replication complexes.
    Keywords:  DNA; Helicase; RNA; RNA polymerase; Single-strand binding protein
    DOI:  https://doi.org/10.1016/bs.enz.2021.07.005
  6. Antioxid Redox Signal. 2021 Oct 29.
    The many roles mitochondria play in mammalian aging.
    Caio M P F Batalha, Anibal Eugênio Vercesi, Nadja C Souza-Pinto.
       SIGNIFICANCE: Aging is a natural process that affects most living organisms, resulting in increased mortality. As the world population ages, the prevalence of age-associated diseases, and their associated healthcare costs, has increased sharply. A better understanding of the molecular mechanisms that lead to cellular dysfunction may provide important targets for interventions to prevent or treat these diseases. Recent Advances: Although the mitochondrial theory of aging has been proposed over 40 years ago, recent new data has given stronger support for a central role for mitochondrial dysfunction in several pathways that are deregulated during normal aging and age-associated disease.
    CRITICAL ISSUES: Several of the experimental evidence linking mitochondrial alterations to age-associated loss of function are correlative and mechanistic insight are still elusive. Here, we review how mitochondrial dysfunction may be involved in many of the known hallmarks of aging, and how these pathways interact in an intricate net of molecular relationships.
    FUTURE DIRECTIONS: As it has become clear that mitochondrial dysfunction plays causative roles in normal aging and age-associated diseases, it is necessary to better define the molecular interactions and the temporal and causal relations between these changes and the relevant phenotypes seen during the aging process.
    DOI:  https://doi.org/10.1089/ars.2021.0074
  7. Yeast. 2021 Oct 28.
    Functional Analyses of Mitoribosome 54S Subunit Devoid of Mitochondria-Specific Protein Sequences.
    Barbara Santos, Rui Zeng, Sasa F Jorge, Jose Ribamar Ferreira-Junior, Antoni Barrientos, Mario H Barros.
      
    Keywords:  Saccharomyces cerevisiae; mitochondria-specific extensions; mitoribosome 54S subunit
    DOI:  https://doi.org/10.1002/yea.3678
  8. Elife. 2021 Oct 26. pii: e70899. [Epub ahead of print]10
    Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures.
    Shannon Rausser, Caroline Trumpff, Marlon A McGill, Alex Junker, Wei Wang, Siu-Hong Ho, Anika Mitchell, Kalpita R Karan, Catherine E Monk, Suzanne C Segerstrom, Rebecca G Reed, Martin Picard.
      Using a high-throughput mitochondrial phenotyping platform to quantify multiple mitochondrial features among molecularly-defined immune cell subtypes, we quantify the natural variation in citrate synthase, mitochondrial DNA copy number (mtDNAcn), and respiratory chain enzymatic activities in human neutrophils, monocytes, B cells, and naïve and memory T lymphocyte subtypes. In mixed peripheral blood mononuclear cells (PBMCs) from the same individuals, we show to what extent mitochondrial measures are confounded by both cell type distributions and contaminating platelets. Cell subtype-specific measures among women and men spanning 4 decades of life indicate potential age- and sex-related differences, including an age-related elevation in mtDNAcn, which are masked or blunted in mixed PBMCs. Finally, a proof-of-concept, repeated-measures study in a single individual validates cell type differences and also reveals week-to-week changes in mitochondrial activities. Larger studies are required to validate and mechanistically extend these findings. These mitochondrial phenotyping data build upon established immunometabolic differences among leukocyte sub-populations, and provide foundational quantitative knowledge to develop interpretable blood-based assays of mitochondrial health.
    Keywords:  cell biology; human; immunology; inflammation
    DOI:  https://doi.org/10.7554/eLife.70899
  9. Dev Cell. 2021 Oct 22. pii: S1534-5807(21)00809-1. [Epub ahead of print]
    Identification of long-lived proteins in the mitochondria reveals increased stability of the electron transport chain.
    Shefali Krishna, Rafael Arrojo E Drigo, Juliana S Capitanio, Ranjan Ramachandra, Mark Ellisman, Martin W Hetzer.
      In order to combat molecular damage, most cellular proteins undergo rapid turnover. We have previously identified large nuclear protein assemblies that can persist for years in post-mitotic tissues and are subject to age-related decline. Here, we report that mitochondria can be long lived in the mouse brain and reveal that specific mitochondrial proteins have half-lives longer than the average proteome. These mitochondrial long-lived proteins (mitoLLPs) are core components of the electron transport chain (ETC) and display increased longevity in respiratory supercomplexes. We find that COX7C, a mitoLLP that forms a stable contact site between complexes I and IV, is required for complex IV and supercomplex assembly. Remarkably, even upon depletion of COX7C transcripts, ETC function is maintained for days, effectively uncoupling mitochondrial function from ongoing transcription of its mitoLLPs. Our results suggest that modulating protein longevity within the ETC is critical for mitochondrial proteome maintenance and the robustness of mitochondrial function.
    Keywords:  age mosaicism; aging; electron transport chain; heterogeneity; long-lived proteins; mitochondria; muscle; neurons; protein homeostasis; supercomplexes
    DOI:  https://doi.org/10.1016/j.devcel.2021.10.008
  10. Nat Metab. 2021 Oct 25.
    Sex-specific genetic regulation of adipose mitochondria and metabolic syndrome by Ndufv2.
    Karthickeyan Chella Krishnan, Laurent Vergnes, Rebeca Acín-Pérez, Linsey Stiles, Michael Shum, Lijiang Ma, Etienne Mouisel, Calvin Pan, Timothy M Moore, Miklós Péterfy, Casey E Romanoski, Karen Reue, Johan L M Björkegren, Markku Laakso, Marc Liesa, Aldons J Lusis.
      We have previously suggested a central role for mitochondria in the observed sex differences in metabolic traits. However, the mechanisms by which sex differences affect adipose mitochondrial function and metabolic syndrome are unclear. Here we show that in both mice and humans, adipose mitochondrial functions are elevated in females and are strongly associated with adiposity, insulin resistance and plasma lipids. Using a panel of diverse inbred strains of mice, we identify a genetic locus on mouse chromosome 17 that controls mitochondrial mass and function in adipose tissue in a sex- and tissue-specific manner. This locus contains Ndufv2 and regulates the expression of at least 89 mitochondrial genes in females, including oxidative phosphorylation genes and those related to mitochondrial DNA content. Overexpression studies indicate that Ndufv2 mediates these effects by regulating supercomplex assembly and elevating mitochondrial reactive oxygen species production, which generates a signal that increases mitochondrial biogenesis.
    DOI:  https://doi.org/10.1038/s42255-021-00481-w
  11. Nucleic Acid Ther. 2021 Oct 25.
    Antisense Oligonucleotide-Mediated Silencing of Mitochondrial Fusion and Fission Factors Modulates Mitochondrial Dynamics and Rescues Mitochondrial Dysfunction.
    Daniel A Garcia, Andrew F Powers, Thomas A Bell, Shuling Guo, Mariam Aghajan.
      Mitochondria are highly dynamic organelles that produce ATP and maintain metabolic, catabolic, and redox homeostasis. Mitochondria owe this dynamic nature to their constant fission and fusion-processes that are regulated, in part, by fusion factors (MFN1 and MFN2) and fission factors (DRP1, FIS1, MFF, MIEF1, MIEF2) located on the outer mitochondrial membrane. While mitochondrial fusion and fission are known to influence mitochondrial morphology and function, a key question is whether rebalancing mitochondrial morphology can ameliorate mitochondrial dysfunction in the context of mitochondrial pathology. In this study, we used antisense oligonucleotides (ASOs) to systematically evaluate the effects of fusion and fission factors in vitro. Free uptake by cells of fusion or fission factor ASOs caused robust decreases in target gene expression and altered a variety of mitochondrial parameters, including mitochondrial size and respiration, which were dose dependent. In Mfn1 knockout mouse embryonic fibroblasts (MEFs) and MFN2-R94Q (Charcot-Marie-Tooth Type 2 Disease-associated mutation) MEFs, two cellular models of mitochondrial dysfunction, we found that ASO-mediated silencing of only Drp1 restored mitochondrial morphology and enhanced mitochondrial respiration. Together, these data demonstrate in vitro proof-of-concept for rebalancing mitochondrial morphology to rescue function using ASOs and suggest that ASO-mediated modulation of mitochondrial dynamics may be a viable therapeutic approach to restore mitochondrial homeostasis in diseases driven by mitochondrial dysfunction.
    Keywords:  antisense; mitochondria; mitochondrial dynamics; oligonucleotides
    DOI:  https://doi.org/10.1089/nat.2021.0029
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