bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023‒04‒09
ten papers selected by
Edmond Chan
Queen’s University, School of Medicine
  1. NAD+ repletion with niacin counteracts cancer cachexia.
  2. Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
  3. The mitochondrial ATP synthase as an ATP consumer-a surprising therapeutic target.
  4. The mitochondrial ribosomal protein mRpL4 regulates Notch signaling.
  5. PGC-1s shape epidermal physiology by modulating keratinocyte proliferation and terminal differentiation.
  6. An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity.
  7. Protein translocation in mitochondria: Sorting out the Toms, Tims, Pams, Sams and Mia.
  8. Metabolic set points of mammalian neurodevelopment.
  9. Mitochondria in Health, Disease, and Ageing.
  10. MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
  1. Nat Commun. 2023 Apr 03. 14(1): 1849
    NAD+ repletion with niacin counteracts cancer cachexia.
    Marc Beltrà, Noora Pöllänen, Claudia Fornelli, Kialiina Tonttila, Myriam Y Hsu, Sandra Zampieri, Lucia Moletta, Samantha Corrà, Paolo E Porporato, Riikka Kivelä, Carlo Viscomi, Marco Sandri, Juha J Hulmi, Roberta Sartori, Eija Pirinen, Fabio Penna.
      Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients.
    DOI:  https://doi.org/10.1038/s41467-023-37595-6
  2. Nat Cell Biol. 2023 Apr 03.
    Metaboverse enables automated discovery and visualization of diverse metabolic regulatory patterns.
    Jordan A Berg, Youjia Zhou, Yeyun Ouyang, Ahmad A Cluntun, T Cameron Waller, Megan E Conway, Sara M Nowinski, Tyler Van Ry, Ian George, James E Cox, Bei Wang, Jared Rutter.
      Metabolism is intertwined with various cellular processes, including controlling cell fate, influencing tumorigenesis, participating in stress responses and more. Metabolism is a complex, interdependent network, and local perturbations can have indirect effects that are pervasive across the metabolic network. Current analytical and technical limitations have long created a bottleneck in metabolic data interpretation. To address these shortcomings, we developed Metaboverse, a user-friendly tool to facilitate data exploration and hypothesis generation. Here we introduce algorithms that leverage the metabolic network to extract complex reaction patterns from data. To minimize the impact of missing measurements within the network, we introduce methods that enable pattern recognition across multiple reactions. Using Metaboverse, we identify a previously undescribed metabolite signature that correlated with survival outcomes in early stage lung adenocarcinoma patients. Using a yeast model, we identify metabolic responses suggesting an adaptive role of citrate homeostasis during mitochondrial dysfunction facilitated by the citrate transporter, Ctp1. We demonstrate that Metaboverse augments the user's ability to extract meaningful patterns from multi-omics datasets to develop actionable hypotheses.
    DOI:  https://doi.org/10.1038/s41556-023-01117-9
  3. EMBO J. 2023 Apr 06. e114141
    The mitochondrial ATP synthase as an ATP consumer-a surprising therapeutic target.
    Gabriel E Valdebenito, Anitta R Chacko, Michael R Duchen.
      The mitochondrial F1 Fo -ATP synthase uses a rotary mechanism to synthesise ATP. This mechanism can, however, also operate in reverse, pumping protons at the expense of ATP, with significant potential implications for mitochondrial and age-related diseases. In a recent study, Acin-Perez et al (2023) use an elegant assay to screen compounds for the capacity to selectively inhibit ATP hydrolysis without affecting ATP synthesis. They show that (+)-epicatechin is one such compound and has significant benefits for cell and tissue function in disease models. These findings signpost a novel therapeutic approach for mitochondrial disease.
    DOI:  https://doi.org/10.15252/embj.2023114141
  4. EMBO Rep. 2023 Apr 03. e55764
    The mitochondrial ribosomal protein mRpL4 regulates Notch signaling.
    Dongqing Mo, Chenglin Liu, Yao Chen, Xinkai Cheng, Jie Shen, Long Zhao, Junzheng Zhang.
      Mitochondrial ribosomal proteins (MRPs) assemble as specialized ribosome to synthesize mtDNA-encoded proteins, which are essential for mitochondrial bioenergetic and metabolic processes. MRPs are required for fundamental cellular activities during animal development, but their roles beyond mitochondrial protein translation are poorly understood. Here, we report a conserved role of the mitochondrial ribosomal protein L4 (mRpL4) in Notch signaling. Genetic analyses demonstrate that mRpL4 is required in the Notch signal-receiving cells to permit target gene transcription during Drosophila wing development. We find that mRpL4 physically and genetically interacts with the WD40 repeat protein wap and activates the transcription of Notch signaling targets. We show that human mRpL4 is capable of replacing fly mRpL4 during wing development. Furthermore, knockout of mRpL4 in zebrafish leads to downregulated expression of Notch signaling components. Thus, we have discovered a previously unknown function of mRpL4 during animal development.
    Keywords:   Drosophila ; Notch; mitochondrial ribosomal protein L4; wap; zebrafish
    DOI:  https://doi.org/10.15252/embr.202255764
  5. iScience. 2023 Apr 21. 26(4): 106314
    PGC-1s shape epidermal physiology by modulating keratinocyte proliferation and terminal differentiation.
    Simon-Pierre Gravel, Youcef Ben Khalifa, Shawn McGuirk, Catherine St-Louis, Karl M Laurin, Émilie Lavallée, Damien Benas, Stéphanie Desbouis, Frédéric Amaral, Damien D'Amours, Lionel Breton, Sibylle Jäger, Julie St-Pierre.
      Skin plays central roles in systemic physiology, and it undergoes significant functional changes during aging. Members of the peroxisome proliferator-activated receptor-gamma coactivator (PGC-1) family (PGC-1s) are key regulators of the biology of numerous tissues, yet we know very little about their impact on skin functions. Global gene expression profiling and gene silencing in keratinocytes uncovered that PGC-1s control the expression of metabolic genes as well as that of terminal differentiation programs. Glutamine emerged as a key substrate promoting mitochondrial respiration, keratinocyte proliferation, and the expression of PGC-1s and terminal differentiation programs. Importantly, gene silencing of PGC-1s reduced the thickness of a reconstructed living human epidermal equivalent. Exposure of keratinocytes to a salicylic acid derivative potentiated the expression of PGC-1s and terminal differentiation genes and increased mitochondrial respiration. Overall, our results show that the PGC-1s are essential effectors of epidermal physiology, revealing an axis that could be targeted in skin conditions and aging.
    Keywords:  dermatology; human metabolism; molecular mechanism of gene regulation; physiology
    DOI:  https://doi.org/10.1016/j.isci.2023.106314
  6. Life Sci Alliance. 2023 Jun;pii: e202201767. [Epub ahead of print]6(6):
    An OMA1 redox site controls mitochondrial homeostasis, sarcoma growth, and immunogenicity.
    Richard Miallot, Virginie Millet, Yann Groult, Angelika Modelska, Lydie Crescence, Sandrine Roulland, Sandrine Henri, Bernard Malissen, Nicolas Brouilly, Laurence Panicot-Dubois, Renaud Vincentelli, Gerlind Sulzenbacher, Pascal Finetti, Aurélie Dutour, Jean-Yves Blay, François Bertucci, Franck Galland, Philippe Naquet.
      Aggressive tumors often display mitochondrial dysfunction. Upon oxidative stress, mitochondria undergo fission through OMA1-mediated cleavage of the fusion effector OPA1. In yeast, a redox-sensing switch participates in OMA1 activation. 3D modeling of OMA1 comforted the notion that cysteine 403 might participate in a similar sensor in mammalian cells. Using prime editing, we developed a mouse sarcoma cell line in which OMA1 cysteine 403 was mutated in alanine. Mutant cells showed impaired mitochondrial responses to stress including ATP production, reduced fission, resistance to apoptosis, and enhanced mitochondrial DNA release. This mutation prevented tumor development in immunocompetent, but not nude or cDC1 dendritic cell-deficient, mice. These cells prime CD8+ lymphocytes that accumulate in mutant tumors, whereas their depletion delays tumor control. Thus, OMA1 inactivation increased the development of anti-tumor immunity. Patients with complex genomic soft tissue sarcoma showed variations in the level of OMA1 and OPA1 transcripts. High expression of OPA1 in primary tumors was associated with shorter metastasis-free survival after surgery, and low expression of OPA1, with anti-tumor immune signatures. Targeting OMA1 activity may enhance sarcoma immunogenicity.
    DOI:  https://doi.org/10.26508/lsa.202201767
  7. FEBS Lett. 2023 Apr 05.
    Protein translocation in mitochondria: Sorting out the Toms, Tims, Pams, Sams and Mia.
    Johannes M Herrmann, Yury Bykov.
      Mitochondria contain 902 (yeast) to 1.136 (mouse, humans) verified proteins. Except for a very small number of mitochondrially encoded core components of the respiratory chain, mitochondrial proteins are encoded by nuclear genes and synthesized in the cytosol. Different import pathways direct proteins to their respective mitochondrial subcompartment (outer membrane, intermembrane space (IMS), inner membrane and matrix). Specific targeting signals in their sequence direct proteins to their target destination and allow the proteins to embark on their respective import pathway. The main import pathways are shown here on the poster and are introduced in the following, using the mitochondrial import system of the baker's yeast Saccharomyces cerevisiae as example. However, the mitochondrial import system of mammalian cells is highly similar and deviates only in minor aspects. Even the mitochondrial import machineries of less closely related eukaryotes, such as plants and trypanosomes, are very similar and adhere to the same general principles.
    Keywords:  Mitochondria; Protein Import; Protein translocation; Translocase of the inner membrane; Translocase of the outer membrane
    DOI:  https://doi.org/10.1002/1873-3468.14614
  8. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00090-6. [Epub ahead of print]35(4): 553-554
    Metabolic set points of mammalian neurodevelopment.
    Fumi Suomi, Anna Rappe, Thomas G McWilliams.
      The human nervous system matures over a protracted developmental time frame relative to other species. What sets the pace of maturation has remained a mystery. In a recent publication in Science, Iwata et al. unearth critical contributions of mitochondrial metabolism in setting the pace of species-specific corticogenesis.
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.012
  9. Physiol Rev. 2023 Apr 06.
    Mitochondria in Health, Disease, and Ageing.
    John S Harrington, Stefan W Ryter, Maria Plataki, David R Price, Augustine M K Choi.
      Mitochondria are well-known as organelles responsible for the maintenance of cellular bioenergetics through the production of ATP. While oxidative phosphorylation may be their most important function, mitochondria are also integral for the synthesis of metabolic precursors, calcium regulation, the production of reactive oxygen species, immune signaling, and apoptosis. Considering the breadth of their responsibilities, mitochondria are fundamental for cellular metabolism and homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger of disease. In this review, we provide a detailed overview of mitochondrial metabolism, cellular bioenergetics, mitochondrial dynamics, autophagy, mitochondrial damage-associated molecular patterns, mitochondria-mediated cell-death pathways, and how mitochondrial dysfunction at any of these levels is associated with disease pathogenesis. Mitochondria-dependent pathways may thereby represent an attractive therapeutic target for ameliorating human disease.
    Keywords:  Apoptosis; Inflammation; Mitochondria; Mitochondrial Dysfunction; Mitophagy
    DOI:  https://doi.org/10.1152/physrev.00058.2021
  10. Autophagy Rep. 2022 ;1(1): 210-213
    MitoSwap - Mitophagy partnered with compensatory mitochondrial biogenesis during stem cell differentiation.
    Priyanka Gajwani, Jalees Rehman.
      Differentiating stem cells must adapt their mitochondrial metabolism to fit the needs of the mature differentiated cell. In a recent study, we observed that during differentiation to an endothelial phenotype, pluripotent stem cell mitochondria are removed by mitophagy, triggering compensatory mitochondrial biogenesis to replenish the mitochondrial pool. We identified the mitochondrial phosphatase PGAM5 as the link between mitophagy and transcription of the mitochondrial biogenesis regulator PPARGC1A/PGC1α in the nucleus. Swapping of mitochondria through the coupled processes of mitophagy and mitochondrial biogenesis lead to enhanced metabolic reprogramming in the differentiated cell.
    Keywords:  CTNNB1/β-catenin; PINK1; PPARGC1A/PGC1α; differentiation; endothelium; mitochondrial biogenesis; mitofusin 2; mitophagy; stem cells
    DOI:  https://doi.org/10.1080/27694127.2022.2071549
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