bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023–04–30
fiveteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Resveratrol Attenuates the Mitochondrial RNA-Mediated Cellular Response to Immunogenic Stress.
  2. Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC.
  3. CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.
  4. POLG genotype influences degree of mitochondrial dysfunction in iPSC derived neural progenitors, but not the parent iPSC or derived glia.
  5. MTSviewer: A database to visualize mitochondrial targeting sequences, cleavage sites, and mutations on protein structures.
  6. iPSC-derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function.
  7. Methodologies in Mitochondrial Testing: Diagnosing a Primary Mitochondrial Respiratory Chain Disorder.
  8. Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction.
  9. MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca2+ uniporter channel.
  10. Pleiotropic effects of mitochondria in aging.
  11. A tissue injury sensing and repair pathway distinct from host pathogen defense.
  12. Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis.
  13. The Warburg effect: a signature of mitochondrial overload.
  14. Efficient engineering of human and mouse primary cells using peptide-assisted genome editing.
  15. Gut mitochondrial defects drive neurodegeneration.
  1. Int J Mol Sci. 2023 Apr 17. pii: 7403. [Epub ahead of print]24(8):
    Resveratrol Attenuates the Mitochondrial RNA-Mediated Cellular Response to Immunogenic Stress.
    Jimin Yoon, Doyeong Ku, Minseok Lee, Namseok Lee, Sung Gap Im, Yoosik Kim.
      Human mitochondria contain a circular genome that encodes 13 subunits of the oxidative phosphorylation system. In addition to their role as powerhouses of the cells, mitochondria are also involved in innate immunity as the mitochondrial genome generates long double-stranded RNAs (dsRNAs) that can activate the dsRNA-sensing pattern recognition receptors. Recent evidence shows that these mitochondrial dsRNAs (mt-dsRNAs) are closely associated with the pathogenesis of human diseases that accompany inflammation and aberrant immune activation, such as Huntington's disease, osteoarthritis, and autoimmune Sjögren's syndrome. Yet, small chemicals that can protect cells from a mt-dsRNA-mediated immune response remain largely unexplored. Here, we investigate the potential of resveratrol (RES), a plant-derived polyphenol with antioxidant properties, on suppressing mt-dsRNA-mediated immune activation. We show that RES can revert the downstream response to immunogenic stressors that elevate mitochondrial RNA expressions, such as stimulation by exogenous dsRNAs or inhibition of ATP synthase. Through high-throughput sequencing, we find that RES can regulate mt-dsRNA expression, interferon response, and other cellular responses induced by these stressors. Notably, RES treatment fails to counter the effect of an endoplasmic reticulum stressor that does not affect the expression of mitochondrial RNAs. Overall, our study demonstrates the potential usage of RES to alleviate the mt-dsRNA-mediated immunogenic stress response.
    Keywords:  Sjögren’s syndrome; dsRNA stress; immunogenic stress; innate immunity; mitochondrial double-stranded RNAs; oligomycin A; resveratrol; tunicamycin
    DOI:  https://doi.org/10.3390/ijms24087403
  2. PLoS Genet. 2023 Apr 25. 19(4): e1010493
    Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC.
    Rajit Narayanan Cheramangalam, Tarana Anand, Priyanka Pandey, Deepa Balasubramanian, Reshmi Varghese, Neha Singhal, Sonal Nagarkar Jaiswal, Manish Jaiswal.
      Cells under mitochondrial stress often co-opt mechanisms to maintain energy homeostasis, mitochondrial quality control and cell survival. A mechanistic understanding of such responses is crucial for further insight into mitochondrial biology and diseases. Through an unbiased genetic screen in Drosophila, we identify that mutations in lrpprc2, a homolog of the human LRPPRC gene that is linked to the French-Canadian Leigh syndrome, result in PINK1-Park activation. While the PINK1-Park pathway is well known to induce mitophagy, we show that PINK1-Park regulates mitochondrial dynamics by inducing the degradation of the mitochondrial fusion protein Mitofusin/Marf in lrpprc2 mutants. In our genetic screen, we also discover that Bendless, a K63-linked E2 conjugase, is a regulator of Marf, as loss of bendless results in increased Marf levels. We show that Bendless is required for PINK1 stability, and subsequently for PINK1-Park mediated Marf degradation under physiological conditions, and in response to mitochondrial stress as seen in lrpprc2. Additionally, we show that loss of bendless in lrpprc2 mutant eyes results in photoreceptor degeneration, indicating a neuroprotective role for Bendless-PINK1-Park mediated Marf degradation. Based on our observations, we propose that certain forms of mitochondrial stress activate Bendless-PINK1-Park to limit mitochondrial fusion, which is a cell-protective response.
    DOI:  https://doi.org/10.1371/journal.pgen.1010493
  3. Nat Aging. 2023 Apr 17.
    CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.
    Jun Jin, Yunmei Mu, Huimin Zhang, Ines Sturmlechner, Chenyao Wang, Rohit R Jadhav, Qiong Xia, Cornelia M Weyand, Jorg J Goronzy.
      Chronic systemic inflammation is one of the hallmarks of the aging immune system. Here we show that activated T cells from older adults contribute to inflammaging by releasing mitochondrial DNA (mtDNA) into their environment due to an increased expression of the cytokine-inducible SH2-containing protein (CISH). CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation, thereby impairing lysosomal function. Impaired lysosomal activity caused intracellular accumulation of multivesicular bodies and amphisomes and the export of their cargos, including mtDNA. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal release. In antigen-specific responses in vivo, CISH-deficient CD4+ T cells released less mtDNA and induced fewer inflammatory cytokines. Attenuating CISH expression may present a promising strategy to reduce inflammation in an immune response of older individuals.
    DOI:  https://doi.org/10.1038/s43587-023-00399-w
  4. Exp Neurol. 2023 Apr 25. pii: S0014-4886(23)00114-0. [Epub ahead of print] 114429
    POLG genotype influences degree of mitochondrial dysfunction in iPSC derived neural progenitors, but not the parent iPSC or derived glia.
    Yu Hong, Cecilie Katrin Kristiansen, Anbin Chen, Gonzalo Sanchez Nido, Lena Elise Høyland, Mathias Ziegler, Gareth John Sullivan, Laurence A Bindoff, Kristina Xiao Liang.
      Diseases caused by POLG mutations are the most common form of mitochondrial disease and associated with phenotypes of varying severity. Clinical studies have shown that patients with compound heterozygous POLG mutations have a lower survival rate than patients with homozygous mutations, but the molecular mechanisms behind this remain unexplored. Using an induced pluripotent stem cell (iPSC) model, we investigate differences between homozygous and compound heterozygous genotypes in different cell types, including patient-specific fibroblasts, iPSCs, and iPSC-derived neural stem cells (NSCs) and astrocytes. We found that compound heterozygous lines exhibited greater impairment of mitochondrial function in NSCs than homozygous NSCs, but not in fibroblasts, iPSCs, or astrocytes. Compared with homozygous NSCs, compound heterozygous NSCs exhibited more severe functional defects, including reduced ATP production, loss of mitochondrial DNA (mtDNA) copy number and complex I expression, disturbance of NAD+ metabolism, and higher ROS levels, which further led to cellular senescence and activation of mitophagy. RNA sequencing analysis revealed greater downregulation of mitochondrial and metabolic pathways, including the citric acid cycle and oxidative phosphorylation, in compound heterozygous NSCs. Our iPSC-based disease model can be widely used to understand the genotype-phenotype relationship of affected brain cells in mitochondrial diseases, and further drug discovery applications.
    Keywords:  Genotype; Mitochondrial function; Neural stem cells; Neuron; POLG
    DOI:  https://doi.org/10.1016/j.expneurol.2023.114429
  5. PLoS One. 2023 ;18(4): e0284541
    MTSviewer: A database to visualize mitochondrial targeting sequences, cleavage sites, and mutations on protein structures.
    Andrew N Bayne, Jing Dong, Saeid Amiri, Sali M K Farhan, Jean-François Trempe.
      Mitochondrial dysfunction is implicated in a wide array of human diseases ranging from neurodegenerative disorders to cardiovascular defects. The coordinated localization and import of proteins into mitochondria are essential processes that ensure mitochondrial homeostasis. The localization and import of most mitochondrial proteins are driven by N-terminal mitochondrial targeting sequences (MTS's), which interact with import machinery and are removed by the mitochondrial processing peptidase (MPP). The recent discovery of internal MTS's-those which are distributed throughout a protein and act as import regulators or secondary MPP cleavage sites-has expanded the role of both MTS's and MPP beyond conventional N-terminal regulatory pathways. Still, the global mutational landscape of MTS's remains poorly characterized, both from genetic and structural perspectives. To this end, we have integrated a variety of tools into one harmonized R/Shiny database called MTSviewer (https://neurobioinfo.github.io/MTSvieweR/), which combines MTS predictions, cleavage sites, genetic variants, pathogenicity predictions, and N-terminomics data with structural visualization using AlphaFold models of human and yeast mitochondrial proteomes. Using MTSviewer, we profiled all MTS-containing proteins across human and yeast mitochondrial proteomes and provide multiple case studies to highlight the utility of this database.
    DOI:  https://doi.org/10.1371/journal.pone.0284541
  6. J Clin Invest. 2023 May 01. pii: e163771. [Epub ahead of print]133(9):
    iPSC-derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function.
    Kevin T Eade, Brendan Robert E Ansell, Sarah Giles, Regis Fallon, Sarah Harkins-Perry, Takayuki Nagasaki, Simone Tzaridis, Martina Wallace, Elizabeth A Mills, Samaneh Farashi, Alec Johnson, Lydia Sauer, Barbara Hart, Elena D Rubio, Melanie Bahlo, Christian Metallo, Rando Allikmets, Marin L Gantner, Paul S Bernstein, Martin Friedlander.
      Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful tool for identifying cellular and molecular mechanisms of disease. Macular telangiectasia type 2 (MacTel) is a rare, late-onset degenerative retinal disease with an extremely heterogeneous genetic architecture, lending itself to the use of iPSCs. Whole-exome sequencing screens and pedigree analyses have identified rare causative mutations that account for less than 5% of cases. Metabolomic surveys of patient populations and GWAS have linked MacTel to decreased circulating levels of serine and elevated levels of neurotoxic 1-deoxysphingolipids (1-dSLs). However, retina-specific, disease-contributing factors have yet to be identified. Here, we used iPSC-differentiated retinal pigmented epithelial (iRPE) cells derived from donors with or without MacTel to screen for novel cell-intrinsic pathological mechanisms. We show that MacTel iRPE cells mimicked the low serine levels observed in serum from patients with MacTel. Through RNA-Seq and gene set enrichment pathway analysis, we determined that MacTel iRPE cells are enriched in cellular stress pathways and dysregulation of central carbon metabolism. Using respirometry and mitochondrial stress testing, we functionally validated that MacTel iRPE cells had a reduction in mitochondrial function that was independent of defects in serine biosynthesis and 1-dSL accumulation. Thus, we identified phenotypes that may constitute alternative disease mechanisms beyond the known serine/sphingolipid pathway.
    Keywords:  Mitochondria; Ophthalmology; Retinopathy; Stem cells; iPS cells
    DOI:  https://doi.org/10.1172/JCI163771
  7. Clin Chem. 2023 Apr 26. pii: hvad037. [Epub ahead of print]
    Methodologies in Mitochondrial Testing: Diagnosing a Primary Mitochondrial Respiratory Chain Disorder.
    Emily L Gill, Jing Wang, Angela N Viaene, Stephen R Master, Rebecca D Ganetzky.
       BACKGROUND: Mitochondria are cytosolic organelles within most eukaryotic cells. Mitochondria generate the majority of cellular energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation (OxPhos). Pathogenic variants in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) lead to defects in OxPhos and physiological malfunctions (Nat Rev Dis Primer 2016;2:16080.). Patients with primary mitochondrial disorders (PMD) experience heterogeneous symptoms, typically in multiple organ systems, depending on the tissues affected by mitochondrial dysfunction. Because of this heterogeneity, clinical diagnosis is challenging (Annu Rev Genomics Hum Genet 2017;18:257-75.). Laboratory diagnosis of mitochondrial disease depends on a multipronged analysis that can include biochemical, histopathologic, and genetic testing. Each of these modalities has complementary strengths and limitations in diagnostic utility.
    CONTENT: The primary focus of this review is on diagnosis and testing strategies for primary mitochondrial diseases. We review tissue samples utilized for testing, metabolic signatures, histologic findings, and molecular testing approaches. We conclude with future perspectives on mitochondrial testing.
    SUMMARY: This review offers an overview of the current biochemical, histologic, and genetic approaches available for mitochondrial testing. For each we review their diagnostic utility including complementary strengths and weaknesses. We identify gaps in current testing and possible future avenues for test development.
    DOI:  https://doi.org/10.1093/clinchem/hvad037
  8. Nat Metab. 2023 Apr;5(4): 546-562
    Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction.
    Anna S Monzel, José Antonio Enríquez, Martin Picard.
      Mitochondria have cell-type specific phenotypes, perform dozens of interconnected functions and undergo dynamic and often reversible physiological recalibrations. Given their multifunctional and malleable nature, the frequently used terms 'mitochondrial function' and 'mitochondrial dysfunction' are misleading misnomers that fail to capture the complexity of mitochondrial biology. To increase the conceptual and experimental specificity in mitochondrial science, we propose a terminology system that distinguishes between (1) cell-dependent properties, (2) molecular features, (3) activities, (4) functions and (5) behaviours. A hierarchical terminology system that accurately captures the multifaceted nature of mitochondria will achieve three important outcomes. It will convey a more holistic picture of mitochondria as we teach the next generations of mitochondrial biologists, maximize progress in the rapidly expanding field of mitochondrial science, and also facilitate synergy with other disciplines. Improving specificity in the language around mitochondrial science is a step towards refining our understanding of the mechanisms by which this unique family of organelles contributes to cellular and organismal health.
    DOI:  https://doi.org/10.1038/s42255-023-00783-1
  9. Sci Signal. 2023 04 25. 16(782): eabi8948
    MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca2+ uniporter channel.
    Dhanendra Tomar, Manfred Thomas, Joanne F Garbincius, Devin W Kolmetzky, Oniel Salik, Pooja Jadiya, Suresh K Joseph, April C Carpenter, György Hajnóczky, John W Elrod.
      MICU1 is a calcium (Ca2+)-binding protein that regulates the mitochondrial Ca2+ uniporter channel complex (mtCU) and mitochondrial Ca2+ uptake. MICU1 knockout mice display disorganized mitochondrial architecture, a phenotype that is distinct from that of mice with deficiencies in other mtCU subunits and, thus, is likely not explained by changes in mitochondrial matrix Ca2+ content. Using proteomic and cellular imaging techniques, we found that MICU1 localized to the mitochondrial contact site and cristae organizing system (MICOS) and directly interacted with the MICOS components MIC60 and CHCHD2 independently of the mtCU. We demonstrated that MICU1 was essential for MICOS complex formation and that MICU1 ablation resulted in altered cristae organization, mitochondrial ultrastructure, mitochondrial membrane dynamics, and cell death signaling. Together, our results suggest that MICU1 is an intermembrane space Ca2+ sensor that modulates mitochondrial membrane dynamics independently of matrix Ca2+ uptake. This system enables distinct Ca2+ signaling in the mitochondrial matrix and at the intermembrane space to modulate cellular energetics and cell death in a concerted manner.
    DOI:  https://doi.org/10.1126/scisignal.abi8948
  10. Nat Aging. 2022 Mar;2(3): 199-213
    Pleiotropic effects of mitochondria in aging.
    Tanes Lima, Terytty Yang Li, Adrienne Mottis, Johan Auwerx.
      Aging is typified by a progressive decline in mitochondrial activity and stress resilience. Here, we review how mitochondrial stress pathways have pleiotropic effects on cellular and systemic homeostasis, which can comprise protective or detrimental responses during aging. We describe recent evidence arguing that defects in these conserved adaptive pathways contribute to aging and age-related diseases. Signaling pathways regulating the mitochondrial unfolded protein response, mitochondrial membrane dynamics, and mitophagy are discussed, emphasizing how their failure contributes to heteroplasmy and de-regulation of key metabolites. Our current understanding of how these processes are controlled and interconnected explains how mitochondria can widely impact fundamental aspects of aging.
    DOI:  https://doi.org/10.1038/s43587-022-00191-2
  11. Cell. 2023 Apr 24. pii: S0092-8674(23)00328-8. [Epub ahead of print]
    A tissue injury sensing and repair pathway distinct from host pathogen defense.
    Siqi Liu, Yun Ha Hur, Xin Cai, Qian Cong, Yihao Yang, Chiwei Xu, Angelina M Bilate, Kevin Andrew Uy Gonzales, S Martina Parigi, Christopher J Cowley, Brian Hurwitz, Ji-Dung Luo, Tiffany Tseng, Shiri Gur-Cohen, Megan Sribour, Tatiana Omelchenko, John Levorse, Hilda Amalia Pasolli, Craig B Thompson, Daniel Mucida, Elaine Fuchs.
      Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.
    Keywords:  STAT3; angiogenesis; coordinated tissue repair; epithelial stem cells; hypoxia; innate immune signaling; interferons; interleukin-24; microbiome-independent responses; tissue injury
    DOI:  https://doi.org/10.1016/j.cell.2023.03.031
  12. Nat Immunol. 2023 Apr 24.
    Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis.
    Yavuz F Yazicioglu, Eros Marin, Ciaran Sandhu, Silvia Galiani, Iwan G A Raza, Mohammad Ali, Barbara Kronsteiner, Ewoud B Compeer, Moustafa Attar, Susanna J Dunachie, Michael L Dustin, Alexander J Clarke.
      Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.
    DOI:  https://doi.org/10.1038/s41590-023-01484-3
  13. Trends Cell Biol. 2023 Apr 26. pii: S0962-8924(23)00070-3. [Epub ahead of print]
    The Warburg effect: a signature of mitochondrial overload.
    Yahui Wang, Gary J Patti.
      A long-standing question in cancer biology has been why oxygenated tumors ferment the majority of glucose they consume to lactate rather than oxidizing it in their mitochondria, a phenomenon known as the 'Warburg effect.' An abundance of evidence shows not only that most cancer cells have fully functional mitochondria but also that mitochondrial activity is important to proliferation. It is therefore difficult to rationalize the metabolic benefit of cancer cells switching from respiration to fermentation. An emerging perspective is that rather than mitochondrial metabolism being suppressed in tumors, as is often suggested, mitochondrial activity increases to the level of saturation. As such, the Warburg effect becomes a signature of excess glucose being released as lactate due to mitochondrial overload.
    Keywords:  Warburg effect; aerobic fermentation; aerobic glycolysis; cancer metabolism; mitochondrial metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2023.03.013
  14. Nat Biotechnol. 2023 Apr 24.
    Efficient engineering of human and mouse primary cells using peptide-assisted genome editing.
    Zhen Zhang, Amy E Baxter, Diqiu Ren, Kunhua Qin, Zeyu Chen, Sierra M Collins, Hua Huang, Chad A Komar, Peter F Bailer, Jared B Parker, Gerd A Blobel, Rahul M Kohli, E John Wherry, Shelley L Berger, Junwei Shi.
      Simple, efficient and well-tolerated delivery of CRISPR genome editing systems into primary cells remains a major challenge. Here we describe an engineered Peptide-Assisted Genome Editing (PAGE) CRISPR-Cas system for rapid and robust editing of primary cells with minimal toxicity. The PAGE system requires only a 30-min incubation with a cell-penetrating Cas9 or Cas12a and a cell-penetrating endosomal escape peptide to achieve robust single and multiplex genome editing. Unlike electroporation-based methods, PAGE gene editing has low cellular toxicity and shows no significant transcriptional perturbation. We demonstrate rapid and efficient editing of primary cells, including human and mouse T cells, as well as human hematopoietic progenitor cells, with editing efficiencies upwards of 98%. PAGE provides a broadly generalizable platform for next-generation genome engineering in primary cells.
    DOI:  https://doi.org/10.1038/s41587-023-01756-1
  15. Nat Aging. 2022 Apr;2(4): 277-279
    Gut mitochondrial defects drive neurodegeneration.
    Ricardo Aparicio, Edward T Schmid, David W Walker.
      
    DOI:  https://doi.org/10.1038/s43587-022-00206-y
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