bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023‒06‒11
nine papers selected by
Marco Tigano
Thomas Jefferson University
  1. A cytosolic surveillance mechanism activates the mitochondrial UPR.
  2. DNA Damage Response and Mitochondrial Translation Mediate ROS Response.
  3. ATF4 regulates mitochondrial content, morphology, and function in differentiating skeletal muscle myotubes.
  4. Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease.
  5. HaploCart: Human mtDNA haplogroup classification using a pangenomic reference graph human mtDNA haplogroup inference.
  6. Mitochondrial dysfunctions induce PANoptosis and ferroptosis in cerebral ischemia/reperfusion injury: from pathology to therapeutic potential.
  7. Activation of cytosolic RNA sensors by endogenous ligands: roles in disease pathogenesis.
  8. The multiple links between actin and mitochondria.
  9. STAT1 is required to establish but not maintain interferon-γ-induced transcriptional memory.
  1. Nature. 2023 Jun 07.
    A cytosolic surveillance mechanism activates the mitochondrial UPR.
    F X Reymond Sutandy, Ines Gößner, Georg Tascher, Christian Münch.
      The mitochondrial unfolded protein response (UPRmt) is essential to safeguard mitochondria from proteotoxic damage by activating a dedicated transcriptional response in the nucleus to restore proteostasis1,2. Yet, it remains unclear how the information on mitochondria misfolding stress (MMS) is signalled to the nucleus as part of the human UPRmt (refs. 3,4). Here, we show that UPRmt signalling is driven by the release of two individual signals in the cytosol-mitochondrial reactive oxygen species (mtROS) and accumulation of mitochondrial protein precursors in the cytosol (c-mtProt). Combining proteomics and genetic approaches, we identified that MMS causes the release of mtROS into the cytosol. In parallel, MMS leads to mitochondrial protein import defects causing c-mtProt accumulation. Both signals integrate to activate the UPRmt; released mtROS oxidize the cytosolic HSP40 protein DNAJA1, which leads to enhanced recruitment of cytosolic HSP70 to c-mtProt. Consequently, HSP70 releases HSF1, which translocates to the nucleus and activates transcription of UPRmt genes. Together, we identify a highly controlled cytosolic surveillance mechanism that integrates independent mitochondrial stress signals to initiate the UPRmt. These observations reveal a link between mitochondrial and cytosolic proteostasis and provide molecular insight into UPRmt signalling in human cells.
    DOI:  https://doi.org/10.1038/s41586-023-06142-0
  2. Cancer Discov. 2023 Jun 09. OF1
    DNA Damage Response and Mitochondrial Translation Mediate ROS Response.
      The cellular response to ROS depends on coordination of activities in the nucleus and mitochondria.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-085
  3. Am J Physiol Cell Physiol. 2023 Jun 05.
    ATF4 regulates mitochondrial content, morphology, and function in differentiating skeletal muscle myotubes.
    Jonathan M Memme, Victoria C Sanfrancesco, David A Hood.
      Mitochondrial function is widely recognized as a major determinant of health, emphasizing the importance of understanding the mechanisms promoting mitochondrial quality in various tissues. Recently, the mitochondrial unfolded protein response (UPRmt) has come into focus as a modulator of mitochondrial homeostasis, particularly in stress conditions. In muscle, the necessity for ATF4 and its role in regulating mitochondrial quality control (MQC) has yet to be determined. We overexpressed (OE) and knocked down ATF4 in C2C12 myoblasts, differentiated them to myotubes for 5 days, and subjected them to acute (ACA) or chronic (CCA) contractile activity. ATF4 mediated myotube formation through the regulated expression of myogenic factors, mainly Myc and MyoD, and supressed mitochondrial biogenesis basally through PGC-1a. However, our data also show that ATF4 expression levels are directly related to mitochondrial fusion and dynamics, UPRmt activation, as well as lysosomal biogenesis and autophagy. Thus, ATF4 promoted enhanced mitochondrial networking, protein handling, and capacity for clearance of dysfunctional organelles under stress conditions, despite lower levels of mitophagy flux with OE. Indeed, we found that ATF4 promoted the formation of a smaller pool of high functioning mitochondria that are more responsive to contractile activity, have higher oxygen consumption rates and lower reactive oxygen species levels. These data provide evidence that ATF4 is both necessary and sufficient for mitochondrial quality control and adaptation during both differentiation and contractile activity, thus advancing the current understanding of ATF4 beyond its canonical functions, to include the regulation of mitochondrial morphology, lysosomal biogenesis and mitophagy in muscle cells.
    Keywords:  ATF4; mitochondrial quality control; mitochondrial unfolded protein response; mitophagy and lysosomal biogenesis; skeletal muscle C2C12
    DOI:  https://doi.org/10.1152/ajpcell.00080.2023
  4. JCI Insight. 2023 Jun 08. pii: e165937. [Epub ahead of print]
    Multimodal single-cell analysis of non-random heteroplasmy distribution in human retinal mitochondrial disease.
    Nathaniel K Mullin, Andrew P Voigt, Miles J Flamme-Wiese, Xiuying Liu, Megan J Riker, Katayoun Varzavand, Edwin M Stone, Budd A Tucker, Robert F Mullins.
      Variants within the high copy number mitochondrial genome (mtDNA) can disrupt organelle function and lead to severe multi-system disease. The wide range of manifestations observed in mitochondrial disease patients results from varying fractions of abnormal mtDNA molecules in different cells and tissues, a phenomenon termed heteroplasmy. However, the landscape of heteroplasmy across cell types within tissues and its influence on phenotype expression in affected patients remains largely unexplored. Here, we identify non-random distribution of a pathogenic mtDNA variant across a complex tissue using single-cell RNA sequencing, mitochondrial single-cell ATAC sequencing, and multimodal single-cell sequencing. We profile the transcriptome, chromatin accessibility state, and heteroplasmy in cells from the eyes of a patient with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and healthy control donors. Utilizing the retina as a model for complex multi-lineage tissues, we found that the proportion of the pathogenic m.3243A>G allele was neither evenly nor randomly distributed across diverse cell types. All neuroectoderm-derived neural cells exhibited a high percentage of the mutant variant. However, a subset of mesoderm-derived lineage, namely the vasculature of the choroid, was near homoplasmic for the wildtype allele. Gene expression and chromatin accessibility profiles of cell types with high and low proportions of m.3243A>G implicate mTOR signaling in the cellular response to heteroplasmy. We further found by multimodal single-cell sequencing of retinal pigment epithelial cells that a high proportion of the pathogenic mtDNA variant was associated with transcriptionally and morphologically abnormal cells. Together, these findings show the non-random nature of mitochondrial variant partitioning in human mitochondrial disease and underscore its implications for mitochondrial disease pathogenesis and treatment.
    Keywords:  Genetic diseases; Genetics; Mitochondria; Ophthalmology; Retinopathy
    DOI:  https://doi.org/10.1172/jci.insight.165937
  5. PLoS Comput Biol. 2023 Jun 07. 19(6): e1011148
    HaploCart: Human mtDNA haplogroup classification using a pangenomic reference graph human mtDNA haplogroup inference.
    Joshua Daniel Rubin, Nicola Alexandra Vogel, Shyam Gopalakrishnan, Peter Wad Sackett, Gabriel Renaud.
      Current mitochondrial DNA (mtDNA) haplogroup classification tools map reads to a single reference genome and perform inference based on the detected mutations to this reference. This approach biases haplogroup assignments towards the reference and prohibits accurate calculations of the uncertainty in assignment. We present HaploCart, a probabilistic mtDNA haplogroup classifier which uses a pangenomic reference graph framework together with principles of Bayesian inference. We demonstrate that our approach significantly outperforms available tools by being more robust to lower coverage or incomplete consensus sequences and producing phylogenetically-aware confidence scores that are unbiased towards any haplogroup. HaploCart is available both as a command-line tool and through a user-friendly web interface. The C++ program accepts as input consensus FASTA, FASTQ, or GAM files, and outputs a text file with the haplogroup assignments of the samples along with the level of confidence in the assignments. Our work considerably reduces the amount of data required to obtain a confident mitochondrial haplogroup assignment.
    DOI:  https://doi.org/10.1371/journal.pcbi.1011148
  6. Front Cell Neurosci. 2023 ;17 1191629
    Mitochondrial dysfunctions induce PANoptosis and ferroptosis in cerebral ischemia/reperfusion injury: from pathology to therapeutic potential.
    Ruining She, Danhong Liu, Jun Liao, Guozuo Wang, Jinwen Ge, Zhigang Mei.
      Ischemic stroke (IS) accounts for more than 80% of the total stroke, which represents the leading cause of mortality and disability worldwide. Cerebral ischemia/reperfusion injury (CI/RI) is a cascade of pathophysiological events following the restoration of blood flow and reoxygenation, which not only directly damages brain tissue, but also enhances a series of pathological signaling cascades, contributing to inflammation, further aggravate the damage of brain tissue. Paradoxically, there are still no effective methods to prevent CI/RI, since the detailed underlying mechanisms remain vague. Mitochondrial dysfunctions, which are characterized by mitochondrial oxidative stress, Ca2+ overload, iron dyshomeostasis, mitochondrial DNA (mtDNA) defects and mitochondrial quality control (MQC) disruption, are closely relevant to the pathological process of CI/RI. There is increasing evidence that mitochondrial dysfunctions play vital roles in the regulation of programmed cell deaths (PCDs) such as ferroptosis and PANoptosis, a newly proposed conception of cell deaths characterized by a unique form of innate immune inflammatory cell death that regulated by multifaceted PANoptosome complexes. In the present review, we highlight the mechanisms underlying mitochondrial dysfunctions and how this key event contributes to inflammatory response as well as cell death modes during CI/RI. Neuroprotective agents targeting mitochondrial dysfunctions may serve as a promising treatment strategy to alleviate serious secondary brain injuries. A comprehensive insight into mitochondrial dysfunctions-mediated PCDs can help provide more effective strategies to guide therapies of CI/RI in IS.
    Keywords:  PANoptosis; PANoptosome; cerebral ischemia/reperfusion injury (CI/RI); ferroptosis; ischemic stroke; mitochondrial dysfunctions
    DOI:  https://doi.org/10.3389/fncel.2023.1191629
  7. Front Immunol. 2023 ;14 1092790
    Activation of cytosolic RNA sensors by endogenous ligands: roles in disease pathogenesis.
    Sarah Straub, Natalia G Sampaio.
      Early detection of infection is a central and critical component of our innate immune system. Mammalian cells have developed specialized receptors that detect RNA with unusual structures or of foreign origin - a hallmark of many virus infections. Activation of these receptors induces inflammatory responses and an antiviral state. However, it is increasingly appreciated that these RNA sensors can also be activated in the absence of infection, and that this 'self-activation' can be pathogenic and promote disease. Here, we review recent discoveries in sterile activation of the cytosolic innate immune receptors that bind RNA. We focus on new aspects of endogenous ligand recognition uncovered in these studies, and their roles in disease pathogenesis.
    Keywords:  LGP2; MDA5; OAS (2′5′-oligoadenylate synthetase); PKR; RIG-I; RNA; ZBP1; interferon
    DOI:  https://doi.org/10.3389/fimmu.2023.1092790
  8. Nat Rev Mol Cell Biol. 2023 Jun 05.
    The multiple links between actin and mitochondria.
    Tak Shun Fung, Rajarshi Chakrabarti, Henry N Higgs.
      Actin plays many well-known roles in cells, and understanding any specific role is often confounded by the overlap of multiple actin-based structures in space and time. Here, we review our rapidly expanding understanding of actin in mitochondrial biology, where actin plays multiple distinct roles, exemplifying the versatility of actin and its functions in cell biology. One well-studied role of actin in mitochondrial biology is its role in mitochondrial fission, where actin polymerization from the endoplasmic reticulum through the formin INF2 has been shown to stimulate two distinct steps. However, roles for actin during other types of mitochondrial fission, dependent on the Arp2/3 complex, have also been described. In addition, actin performs functions independent of mitochondrial fission. During mitochondrial dysfunction, two distinct phases of Arp2/3 complex-mediated actin polymerization can be triggered. First, within 5 min of dysfunction, rapid actin assembly around mitochondria serves to suppress mitochondrial shape changes and to stimulate glycolysis. At a later time point, at more than 1 h post-dysfunction, a second round of actin polymerization prepares mitochondria for mitophagy. Finally, actin can both stimulate and inhibit mitochondrial motility depending on the context. These motility effects can either be through the polymerization of actin itself or through myosin-based processes, with myosin 19 being an important mitochondrially attached myosin. Overall, distinct actin structures assemble in response to diverse stimuli to affect specific changes to mitochondria.
    DOI:  https://doi.org/10.1038/s41580-023-00613-y
  9. EMBO J. 2023 Jun 05. e112259
    STAT1 is required to establish but not maintain interferon-γ-induced transcriptional memory.
    Sahar Sh Tehrani, Pawel Mikulski, Izma Abdul-Zani, João F Mata, Wojciech Siwek, Lars Et Jansen.
      Exposure of human cells to interferon-γ (IFNγ) results in a mitotically heritable yet reversible state called long-term transcriptional memory. We previously identified the clustered GBP genes as strongly primed by IFNγ. Here, we discovered that in primed cells, both interferon-responsive transcription factors STAT1 and IRF1 target chromatin with accelerated kinetics upon re-exposure to IFNγ, specifically at promotors of primed genes. Priming does not alter the degree of IFNγ-induced STAT1 activation or nuclear import, indicating that memory does not alter upstream JAK-STAT signaling. We found STAT1 to be critical to establish transcriptional memory but in a manner that is independent of mere transcription activation. Interestingly, while Serine 727 phosphorylation of STAT1 was maintained during the primed state, STAT1 is not required for the heritability of GBP gene memory. Our results suggest that the memory of interferon exposure constitutes a STAT1-mediated, heritable state that is established during priming. This renders GBP genes poised for subsequent STAT1 and IRF1 binding and accelerated gene activation upon a secondary interferon exposure.
    Keywords:  GBPs; IRF1; STAT1; epigenetic memory; epigenetics; trained immunity
    DOI:  https://doi.org/10.15252/embj.2022112259
This page is being maintained by Thomas Krichel. It was last updated on 2023‒07‒03 at 14:29:31.