bims-mitran Biomed News
on Mitochondrial Translation
Issue of 2023‒11‒12
six papers selected by
Andreas Kohler, Umeå University
  1. Spatially resolved mapping of proteome turnover dynamics with subcellular precision.
  2. Mitochondrial DNA-triggered innate immune response: mechanisms and diseases.
  3. ER-mitochondria contact sites in mitochondrial DNA dynamics, maintenance, and distribution.
  4. Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.
  5. A High-Efficiency Capture-Based NGS Approach for Comprehensive Analysis of Mitochondrial Transcriptome.
  6. Disproportionate role of nuclear-encoded proteins in organismal and mitochondrial thermal performance in a copepod.
  1. Nat Commun. 2023 Nov 08. 14(1): 7217
    Spatially resolved mapping of proteome turnover dynamics with subcellular precision.
    Feng Yuan, Yi Li, Xinyue Zhou, Peiyuan Meng, Peng Zou.
      Cellular activities are commonly associated with dynamic proteomic changes at the subcellular level. Although several techniques are available to quantify whole-cell protein turnover dynamics, such measurements often lack sufficient spatial resolution at the subcellular level. Herein, we report the development of prox-SILAC method that combines proximity-dependent protein labeling (APEX2/HRP) with metabolic incorporation of stable isotopes (pulse-SILAC) to map newly synthesized proteins with subcellular spatial resolution. We apply prox-SILAC to investigate proteome dynamics in the mitochondrial matrix and the endoplasmic reticulum (ER) lumen. Our analysis reveals a highly heterogeneous distribution in protein turnover dynamics within macromolecular machineries such as the mitochondrial ribosome and respiratory complexes I-V, thus shedding light on their mechanism of hierarchical assembly. Furthermore, we investigate the dynamic changes of ER proteome when cells are challenged with stress or undergoing stimulated differentiation, identifying subsets of proteins with unique patterns of turnover dynamics, which may play key regulatory roles in alleviating stress or promoting differentiation. We envision that prox-SILAC could be broadly applied to profile protein turnover at various subcellular compartments, under both physiological and pathological conditions.
    DOI:  https://doi.org/10.1038/s41467-023-42861-8
  2. Cell Mol Immunol. 2023 Nov 07.
    Mitochondrial DNA-triggered innate immune response: mechanisms and diseases.
    Ming-Ming Hu, Hong-Bing Shu.
      Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by the cGAS-MITA/STING pathway, resulting in the induced expression of type I interferon and other effector genes. These processes contribute to the innate immune response to viral infection and other stress factors. The deregulation of these processes causes autoimmune diseases, inflammatory metabolic disorders and cancer. Therefore, the cGAS-MITA/STING pathway is a potential target for intervention in infectious, inflammatory and autoimmune diseases as well as cancer. In this review, we focus on the mechanisms underlying the mtDNA-triggered activation of the cGAS-MITA/STING pathway, the effects of the pathway under various physiological and pathological conditions, and advances in the development of drugs that target cGAS and MITA/STING.
    Keywords:  Disease; Innate immunity; MITA/STING; Mitostress; Virus
    DOI:  https://doi.org/10.1038/s41423-023-01086-x
  3. Int J Biochem Cell Biol. 2023 Nov 04. pii: S1357-2725(23)00131-0. [Epub ahead of print] 106492
    ER-mitochondria contact sites in mitochondrial DNA dynamics, maintenance, and distribution.
    Hema Saranya Ilamathi, Marc Germain.
      Mitochondria are central cellular metabolic hubs. Their function requires proteins encoded by nuclear DNA, but also mitochondrial DNA (mtDNA) whose maintenance is essential for the proper function of the organelle. Defective mtDNA maintenance and distribution are associated with mitochondrial diseases. mtDNA is organized into nucleo-protein complexes called nucleoids that dynamically move along the mitochondrial network and interact with each other. mtDNA replication and nucleoid distribution is an active process regulated by the complex interplay of mitochondrial dynamics, endoplasmic reticulum (ER)-mitochondria contact sites, and cytoskeletal networks. For example, defects in mitochondrial fusion and fission or ER-mitochondria contact sites affect nucleoid maintenance and distribution. In this review, we discuss the process of nucleoid dynamics and the factors regulating nucleoid maintenance and distribution.
    Keywords:  ER sheets; ERMCS; mitochondria; mtDNA-nucleoid
    DOI:  https://doi.org/10.1016/j.biocel.2023.106492
  4. Cytotherapy. 2023 Nov 06. pii: S1465-3249(23)01076-9. [Epub ahead of print]
    Development of mitochondrial gene-editing strategies and their potential applications in mitochondrial hereditary diseases: a review.
    Yanyan Gao, Linlin Guo, Fei Wang, Yin Wang, Peifeng Li, Dejiu Zhang.
      Mitochondrial DNA (mtDNA) is a critical genome contained within the mitochondria of eukaryotic cells, with many copies present in each mitochondrion. Mutations in mtDNA often are inherited and can lead to severe health problems, including various inherited diseases and premature aging. The lack of efficient repair mechanisms and the susceptibility of mtDNA to damage exacerbate the threat to human health. Heteroplasmy, the presence of different mtDNA genotypes within a single cell, increases the complexity of these diseases and requires an effective editing method for correction. Recently, gene-editing techniques, including programmable nucleases such as restriction endonuclease, zinc finger nuclease, transcription activator-like effector nuclease, clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated 9 and base editors, have provided new tools for editing mtDNA in mammalian cells. Base editors are particularly promising because of their high efficiency and precision in correcting mtDNA mutations. In this review, we discuss the application of these techniques in mitochondrial gene editing and their limitations. We also explore the potential of base editors for mtDNA modification and discuss the opportunities and challenges associated with their application in mitochondrial gene editing. In conclusion, this review highlights the advancements, limitations and opportunities in current mitochondrial gene-editing technologies and approaches. Our insights aim to stimulate the development of new editing strategies that can ultimately alleviate the adverse effects of mitochondrial hereditary diseases.
    Keywords:  DddA-derived cytosine base editors (DdCBEs); adenoviruses; mitochondrial DNA (mtDNA); mitochondrially targeted nucleases; mtDNA editing technology; mtDNA heteroplasmy
    DOI:  https://doi.org/10.1016/j.jcyt.2023.10.004
  5. Anal Chem. 2023 Nov 08.
    A High-Efficiency Capture-Based NGS Approach for Comprehensive Analysis of Mitochondrial Transcriptome.
    Zhenni Wang, Kaixiang Zhou, Qing Yuan, Dongbo Chen, Xi'e Hu, Fanfan Xie, Yang Liu, Jinliang Xing.
      The transcription of the mitochondrial genome is pivotal for maintenance of mitochondrial functions, and the deregulated mitochondrial transcriptome contributes to various pathological changes. Despite substantial progress having been achieved in uncovering the transcriptional complexity of the nuclear transcriptome, many unknowns and controversies remain for the mitochondrial transcriptome, partially owing to the lack of a highly efficient mitochondrial RNA (mtRNA) sequencing and analysis approach. Here, we first comprehensively evaluated the influence of essential experimental protocols, including strand-specific library construction, two RNA enrichment strategies, and optimal rRNA depletion, on accurately profiling mitochondrial transcriptome in whole-transcriptome sequencing (WTS) data. Based on these insights, we developed a highly efficient approach specifically suitable for targeted sequencing of whole mitochondrial transcriptome, termed capture-based mtRNA seq (CAP), in which strand-specific library construction and optimal rRNA depletion were applied. Compared with WTS, CAP has a great decrease of required data volume without affecting the sensitivity and accuracy of detection. In addition, CAP also characterized the unannotated mt-tRNA transcripts whose expression levels are below the detection limits of conventional WTS. As a proof-of-concept characterization of mtRNAs, the transcription initiation sites and mtRNA cleavage ratio were accurately identified in CAP data. Moreover, CAP had very reliable performance in plasma and single-cell samples, highlighting its wide application. Altogether, the present study has established a highly efficient pipeline for targeted sequencing of mtRNAs, which may pave the way toward functional annotation of mtRNAs and mtRNA-based diagnostic and therapeutic strategies in various diseases.
    DOI:  https://doi.org/10.1021/acs.analchem.3c03741
  6. J Exp Biol. 2023 Nov 10. pii: jeb.246085. [Epub ahead of print]
    Disproportionate role of nuclear-encoded proteins in organismal and mitochondrial thermal performance in a copepod.
    Kamron L Kayhani, Felipe S Barreto.
      Determining the mechanisms by which organisms evolve thermal tolerance is crucial to predicting how populations may respond to changes in local temperature regimes. While evidence of relationships between mitochondrial background and thermal adaptation have been found, the presence of both nuclear-encoded and mitochondrial DNA (mtDNA)-encoded proteins warrants experiments aimed at parsing out the relative role of each genome in thermal adaptation. We investigate the relative role of mtDNA-encoded products in thermal tolerance between two divergent populations of Tigriopus californicus using first generation (F1) hybrids that vary in maternally inherited mtDNA but are heterozygous for population-specific alleles across nuclear loci. We tested two measures of thermal tolerance: (1) survivorship to acute thermal stress and (2) thermal stability of mitochondrial performance in Complex I-fueled ATP synthesis, both across a range of increasing temperatures. We found that the southern population (San Diego, California) outperformed the northern population (Strawberry Hill, Oregon) in survivorship, and that both reciprocal F1 hybrid crosses had intermediate survival. Mitochondria from the San Diego population displayed greater stability in ATP synthesis with increasing temperatures compared to those from Strawberry Hill. Interestingly, hybrids from both cross directions had synthesis profiles that were very similar to that of Strawberry Hill. Taken together, these results suggest that the relative role of the mtDNA in these phenotypes is negligible compared to that of elements encoded by nuclear DNA in this system.
    Keywords:  Adaptation; Hybridization; Mitochondria; Thermal tolerance
    DOI:  https://doi.org/10.1242/jeb.246085
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