bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023–04–30
seven papers selected by
Avinash N. Mukkala, University of Toronto
  1. FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels.
  2. Bendless is essential for PINK1-Park mediated Mitofusin degradation under mitochondrial stress caused by loss of LRPPRC.
  3. Multifaceted mitochondria: moving mitochondrial science beyond function and dysfunction.
  4. Sodium thiosulfate refuels the hepatic antioxidant pool reducing ischemia-reperfusion-induced liver injury.
  5. MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca2+ uniporter channel.
  6. Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis.
  7. Identification of distinct immune infiltration and potential biomarkers in patients with liver ischemia-reperfusion injury.
  1. EMBO J. 2023 Apr 27. e112799
    FBXL4 ubiquitin ligase deficiency promotes mitophagy by elevating NIX levels.
    Hannah Elcocks, Ailbhe J Brazel, Katy R McCarron, Manuel Kaulich, Koraljka Husnjak, Heather Mortiboys, Michael J Clague, Sylvie Urbé.
      Selective autophagy of mitochondria, mitophagy, is linked to mitochondrial quality control and as such is critical to a healthy organism. We have used a CRISPR/Cas9 approach to screen human E3 ubiquitin ligases for influence on mitophagy under both basal cell culture conditions and upon acute mitochondrial depolarization. We identify two cullin-RING ligase substrate receptors, VHL and FBXL4, as the most profound negative regulators of basal mitophagy. We show that these converge, albeit via different mechanisms, on control of the mitophagy adaptors BNIP3 and BNIP3L/NIX. FBXL4 restricts NIX and BNIP3 levels via direct interaction and protein destabilization, while VHL acts through suppression of HIF1α-mediated transcription of BNIP3 and NIX. Depletion of NIX but not BNIP3 is sufficient to restore mitophagy levels. Our study contributes to an understanding of the aetiology of early-onset mitochondrial encephalomyopathy that is supported by analysis of a disease-associated mutation. We further show that the compound MLN4924, which globally interferes with cullin-RING ligase activity, is a strong inducer of mitophagy, thus providing a research tool in this context and a candidate therapeutic agent for conditions linked to mitochondrial dysfunction.
    Keywords:  BNIP3; FBXL4; NIX; VHL; mitophagy
    DOI:  https://doi.org/10.15252/embj.2022112799
  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 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
  4. Free Radic Biol Med. 2023 Apr 25. pii: S0891-5849(23)00382-9. [Epub ahead of print]
    Sodium thiosulfate refuels the hepatic antioxidant pool reducing ischemia-reperfusion-induced liver injury.
    Adrian T Press, Luisa Ungelenk, Anna Medyukhina, Samantha A Pennington, Sandor Nietzsche, Chunyi Kan, Amelie Lupp, Uta Dahmen, Rui Wang, Utz Settmacher, Reinhard Wetzker, Marc Thilo Figge, Mark G Clemens, Michael Bauer.
      Ischemia-reperfusion injury is a critical liver condition during hepatic transplantation, trauma, or shock. An ischemic deprivation of antioxidants and energy characterizes liver injury in such cases. In the face of increased reactive oxygen production, hepatocytes are vulnerable to the reperfusion driving ROS generation and multiple cell-death mechanisms. In this study, we investigate the importance of hydrogen sulfide as part of the liver's antioxidant pool and the therapeutic potency of the hydrogen sulfide donors sodium sulfide (Na2S, fast releasing) and sodium thiosulfate (STS, Na2S2O3, slow releasing). The mitoprotection and toxicity of STS and Na2S were investigated on isolated mitochondria and a liver perfusion oxidative stress model by adding text-butyl hydroperoxide and hydrogen sulfide donors. The respiratory capacity of mitochondria, hepatocellular released LDH, glutathione, and lipid-peroxide levels were quantified. In addition, wild-type and cystathionine-γ-lyase knockout mice were subjected to warm selective ischemia-reperfusion injury by clamping the main inflow for 1 h followed by reperfusion of 1 or 24 h. A subset of animals was treated with STS shortly before reperfusion. Glutathione, plasma ALT, and lipid-peroxide levels were investigated alongside mitochondrial changes in structure (electron microscopy) and function (intravital microscopy). Liver tissue necrosis quantified 24 h after reperfusion indicates the net effects of the treatment on the organ. STS refuels and protects the endogenous antioxidant pool during liver ischemia-reperfusion injury. In addition, STS-mediated ROS scavenging significantly reduced lipid peroxidation and mitochondrial damage, resulting in better molecular and histopathological preservation of the liver tissue architecture. STS prevents tissue damage in liver ischemia-reperfusion injury by increasing the liver's antioxidant pool, thereby protecting mitochondrial integrity.
    Keywords:  Antioxidants; Hydrogen sulfide; Ischemia-reperfusion injury; Liver; Reactive oxygen species; Sodium thiosulfate
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.04.012
  5. 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
  6. 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
  7. Life Sci. 2023 Apr 25. pii: S0024-3205(23)00360-0. [Epub ahead of print] 121726
    Identification of distinct immune infiltration and potential biomarkers in patients with liver ischemia-reperfusion injury.
    Zhangliu Jin, Meng Dou, Weihui Peng, Boen Xiao, Jinjin Liu, Wen Meng, Wei Liu.
       AIMS: To identify alterations of specific gene expression, immune infiltration components, and potential biomarkers in liver ischemia-reperfusion injury (IRI) following liver transplantation (LT).
    MATERIALS AND METHODS: GSE23649 and GSE151648 datasets were obtained from the Gene Expression Omnibus (GEO) database. To determine the differentially expressed genes (DEGs), we utilized the R package "limma". We also identify the infiltration of different immune cells through single-sample gene-set enrichment analysis (ssGSEA). Furthermore, we utilized LASSO logistic regression to select feature genes and Spearman's rank correlation analysis to determine the correlation between these genes and infiltrating immune cells. Finally, the significance of these feature genes was confirmed using a mouse model of hepatic IRI.
    KEY FINDINGS: A total of 17 DEGs were acquired, most of which were associated with inflammation, apoptosis, cell proliferation, immune disorders, stress response, and angiogenesis. 28 immune cell types were determined using ssGSEA. 5 feature genes (ADM, KLF6, SERPINE1, SLC20A1, and HBB) were screened using LASSO analysis, but the HBB gene was ultimately excluded due to the lack of statistical significance in the GSE151648 dataset. These 4 feature genes were predominantly related to immune cells. Finally, 15 significantly distinctive types of immune cells between the control and IRI groups were verified.
    SIGNIFICANCE: We unveiled that macrophages, dendritic cells (DCs), neutrophils, CD4 T cells, and other immune cells infiltrated the IRI that occurred after LT. Moreover, we identified ADM, KLF6, SERPINE1, and SLC20A1 as potential biological biomarkers underlying IRI post-transplant, which may improve the diagnosis and prognosis of this condition.
    Keywords:  Bioinformatics; Immunity; Inflammation; Ischemia and reperfusion injury; Liver transplantation
    DOI:  https://doi.org/10.1016/j.lfs.2023.121726
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