bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022–09–18
seven papers selected by
Avinash N. Mukkala, University of Toronto
  1. TRIM27 is an autophagy substrate facilitating mitochondria clustering and mitophagy via phosphorylated TBK1.
  2. Calcium homeostasis in the control of mitophagy.
  3. OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.
  4. Mitochondrial stress induces AREG expression and epigenomic remodeling through c-JUN and YAP-mediated enhancer activation.
  5. Mitochondria transfer mediates stress erythropoiesis by altering the bioenergetic profiles of early erythroblasts through CD47.
  6. Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation.
  7. Itaconic acid facilitates inflammation abatement and alleviates liver ischemia-reperfusion injury by inhibiting NF-κB/NLRP3/caspase-1 inflammasome axis.
  1. FEBS J. 2022 Sep 16.
    TRIM27 is an autophagy substrate facilitating mitochondria clustering and mitophagy via phosphorylated TBK1.
    Juncal Garcia-Garcia, Anne Kristin McLaren Berge, Katrine Stange Overå, Kenneth Bowitz Larsen, Zambarlal Bhujabal, Andreas Brech, Yakubu Princely Abudu, Trond Lamark, Terje Johansen, Eva Sjøttem.
      Tripartite motif containing protein 27 (TRIM27/also called RFP) is a multifunctional ubiquitin E3 ligase involved in numerous cellular functions, such as proliferation, apoptosis, regulation of the NF-kB pathway, endosomal recycling, and the innate immune response. TRIM27 interacts directly with TANK-binding kinase 1 (TBK1) and regulates its stability. TBK1 in complex with autophagy receptors are recruited to ubiquitin chains assembled on the mitochondrial outer membrane promoting mitophagy. Here we identify TRIM27 as an autophagy substrate, depending on ATG7, ATG9 and autophagy receptors for its lysosomal degradation. We show that TRIM27 forms ubiquitylated cytoplasmic bodies that colocalize with autophagy receptors. Surprisingly, we observed that induced expression of EGFP-TRIM27 in HEK293 FlpIn TRIM27 Knock-Out cells mediates mitochondrial clustering. TRIM27 interacts with autophagy receptor SQSTM1/p62, and the TRIM27 mediated mitochondrial clustering is facilitated by SQSTM/p62. We show that phosphorylated TBK1 is recruited to the clustered mitochondria. Moreover, induced mitophagy activity is reduced in HEK293 FlpIn TRIM27 Knock Out cells, while re-introduction of EGFP-TRIM27 completely restores the mitophagy activity. Inhibition of TBK1 reduces mitophagy in HEK293 FlpIn cells and in the reconstituted EGFP-TRIM27 expressing cells, but not in HEK293 FlpIn TRIM27 Knock Out cells. Altogether, these data reveal novel roles for TRIM27 in mitophagy, facilitating mitochondrial clustering via SQSTM1/p62 and mitophagy via stabilization of phosphorylated TBK1 on mitochondria.
    DOI:  https://doi.org/10.1111/febs.16628
  2. Antioxid Redox Signal. 2022 Sep 16.
    Calcium homeostasis in the control of mitophagy.
    Mariasole Perrone, Simone Patergnani, Tommaso Di Mambro, Laura Palumbo, Mariusz Więckowski, Carlotta Giorgi, Paolo Pinton.
       SIGNIFICANCE: Maintenance of mitochondrial quality is essential for cellular homeostasis. Among processes responsible for preserving healthy mitochondria, mitophagy selectively eliminates dysfunctional mitochondria by targeting them to the autophagosome for degradation. Alterations in mitophagy lead to the accumulation of damaged mitochondria, which plays an essential role in several diseases like carcinogenesis and tumor progression, neurodegenerative disorders, and autoimmune and cardiovascular pathologies.
    RECENT ADVANCES: Calcium (Ca2+) plays a fundamental role in cell life, modulating several pathways, such as gene expression, proliferation, differentiation, metabolism, cell death, and survival. Indeed, because it is involved in all these events, Ca2+ is the most versatile intracellular second messenger. Being a process that limits cellular degeneration, mitophagy participates in cellular fate decisions. Several mitochondrial parameters, such as membrane potential, structure, and reactive oxygen species, can trigger the activation of mitophagic machinery. These parameters regulate not only mitophagy but also the mitochondrial Ca2+ uptake.
    CRITICAL ISSUES: Ca2+ handling is fundamental in regulating ATP production by mitochondria and mitochondrial quality control processes. Despite the growing literature about the link between Ca2+ and mitophagy, the mechanism by which Ca2+ homeostasis regulates mitophagy is still debated.
    FUTURE DIRECTIONS: Several studies have revealed that excessive mitophagy together with altered mitochondrial Ca2+ uptake leads to different dysfunctions in numerous diseases. Thus, therapeutic modulation of these pathways is considered promising treatments.
    DOI:  https://doi.org/10.1089/ars.2022.0122
  3. Cell Metab. 2022 Sep 08. pii: S1550-4131(22)00360-6. [Epub ahead of print]
    OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.
    Sofia Ahola, Pablo Rivera Mejías, Steffen Hermans, Srikanth Chandragiri, Patrick Giavalisco, Hendrik Nolte, Thomas Langer.
      Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that the cardiac-specific loss of the assembly factor Cox10 of the cytochrome c oxidase causes mitochondrial cardiomyopathy in mice, which is associated with OXPHOS deficiency, lysosomal defects, and an aberrant mitochondrial morphology. Activation of the mitochondrial peptidase Oma1 in Cox10-/- mice results in mitochondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signaling axis. Ablation of Oma1 or Dele1 in Cox10-/- mice aggravates cardiomyopathy. ISR inhibition impairs the cardiac glutathione metabolism, limits the selenium-dependent accumulation of the glutathione peroxidase Gpx4, and increases lipid peroxidation in the heart, ultimately culminating in ferroptosis. Our results demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.
    Keywords:  Atf4; Dele1; Gpx4; Oma1; cardiomyopathy; ferroptosis; glutathione; integrated stress response; mitochondria; selenium
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.017
  4. Nucleic Acids Res. 2022 Sep 12. pii: gkac735. [Epub ahead of print]
    Mitochondrial stress induces AREG expression and epigenomic remodeling through c-JUN and YAP-mediated enhancer activation.
    Yuko Hino, Katsuya Nagaoka, Shinya Oki, Kan Etoh, Shinjiro Hino, Mitsuyoshi Nakao.
      Nucleus-mitochondria crosstalk is essential for cellular and organismal homeostasis. Although anterograde (nucleus-to-mitochondria) pathways have been well characterized, retrograde (mitochondria-to-nucleus) pathways remain to be clarified. Here, we found that mitochondrial dysfunction triggered a retrograde signaling via unique transcriptional and chromatin factors in hepatic cells. Our transcriptomic analysis revealed that the loss of mitochondrial transcription factor A led to mitochondrial dysfunction and dramatically induced expression of amphiregulin (AREG) and other secretory protein genes. AREG expression was also induced by various mitochondria stressors and was upregulated in murine liver injury models, suggesting that AREG expression is a hallmark of mitochondrial damage. Using epigenomic and informatic approaches, we identified that mitochondrial dysfunction-responsive enhancers of AREG gene were activated by c-JUN/YAP1/TEAD axis and were repressed by chromatin remodeler BRG1. Furthermore, while mitochondrial dysfunction-activated enhancers were enriched with JUN and TEAD binding motifs, the repressed enhancers possessed the binding motifs for hepatocyte nuclear factor 4α, suggesting that both stress responsible and cell type-specific enhancers were reprogrammed. Our study revealed that c-JUN and YAP1-mediated enhancer activation shapes the mitochondrial stress-responsive phenotype, which may shift from metabolism to stress adaptation including protein secretion under such stressed conditions.
    DOI:  https://doi.org/10.1093/nar/gkac735
  5. J Exp Med. 2022 Dec 05. pii: e20220685. [Epub ahead of print]219(12):
    Mitochondria transfer mediates stress erythropoiesis by altering the bioenergetic profiles of early erythroblasts through CD47.
    Chong Yang, Rui Yokomori, Lee Hui Chua, Shi Hao Tan, Darren Qiancheng Tan, Kenichi Miharada, Takaomi Sanda, Toshio Suda.
      Intercellular mitochondria transfer is a biological phenomenon implicated in diverse biological processes. However, the physiological role of this phenomenon remains understudied between erythroblasts and their erythroblastic island (EBI) macrophage niche. To gain further insights into the mitochondria transfer functions, we infused EBI macrophages in vivo into mice subjected to different modes of anemic stresses. Interestingly, we observed the occurrence of mitochondria transfer events from the infused EBI macrophages to early stages of erythroblasts coupled with enhanced erythroid recovery. Single-cell RNA-sequencing analysis on erythroblasts receiving exogenous mitochondria revealed a subset of highly proliferative and metabolically active erythroid populations marked by high expression of CD47. Furthermore, CD47 or Sirpα blockade leads to a decline in both the occurrence of mitochondria transfer events and their mediated erythroid recovery. Hence, these data indicate a significant role of mitochondria transfer in the enhancement of erythroid recovery from stress through the alteration of the bioenergetic profiles via CD47-Sirpα interaction in the early stages of erythroblasts.
    DOI:  https://doi.org/10.1084/jem.20220685
  6. J Cell Biol. 2022 Nov 07. pii: e202201160. [Epub ahead of print]221(11):
    Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation.
    Rajarshi Chakrabarti, Tak Shun Fung, Taewook Kang, Pieti W Elonkirjo, Anu Suomalainen, Edward J Usherwood, Henry N Higgs.
      Mitochondrial damage represents a dramatic change in cellular homeostasis. One rapid response is perimitochondrial actin polymerization, termed acute damage-induced actin (ADA). The consequences of ADA are not understood. In this study, we show evidence suggesting that ADA is linked to rapid glycolytic activation upon mitochondrial damage in multiple cells, including mouse embryonic fibroblasts and effector CD8+ T lymphocytes. ADA-inducing treatments include CCCP, antimycin, rotenone, oligomycin, and hypoxia. The Arp2/3 complex inhibitor CK666 or the mitochondrial sodium-calcium exchanger (NCLX) inhibitor CGP37157 inhibits both ADA and the glycolytic increase within 5 min, supporting ADA's role in glycolytic stimulation. Two situations causing chronic reductions in mitochondrial ATP production, mitochondrial DNA depletion and mutation to the NDUFS4 subunit of complex 1 of the electron transport chain, cause persistent perimitochondrial actin filaments similar to ADA. CK666 treatment causes rapid mitochondrial actin loss and a drop in ATP in NDUFS4 knock-out cells. We propose that ADA is necessary for rapid glycolytic activation upon mitochondrial impairment, to re-establish ATP production.
    DOI:  https://doi.org/10.1083/jcb.202201160
  7. Ann Transl Med. 2022 Aug;10(16): 861
    Itaconic acid facilitates inflammation abatement and alleviates liver ischemia-reperfusion injury by inhibiting NF-κB/NLRP3/caspase-1 inflammasome axis.
    Ensi Ma, Hao Xing, Jiahao Pei, Quanbao Zhang, Ruidong Li, Conghuan Shen, Yifeng Tao, Jianhua Li, Zhenyu Ma, Jing Zhao, Zhengxin Wang.
       Background: Ischemia-reperfusion injury (IRI) severely limits the efficacy and donor source of liver transplantation, and the crucial step in alleviating it is to control inflammation. Itaconic acid is a metabolite produced by intrinsic immune cells (especially macrophages) in the inflammatory state and can promote inflammation subsidence. However, its role in liver ischemia-reperfusion is insufficiently clarified.
    Methods: A mouse liver ischemia-reperfusion model was constructed, and blood and liver tissue samples were collected by sequential euthanasia of mice at pre-set time points. Liver function and inflammatory factor concentrations were measured, and HE staining was conducted. In the hypoxia-reoxygenation model, proteins were collected at pre-set time points, and the expression of NF-κB pathway-associated protein and its downstream inflammation-associated protein NLRP3 and caspase-1 were detected by Western blot, immunohistochemistry, and immunofluorescence. The level of P-P65 in the nucleus was detected by immunofluorescence.
    Results: In the liver ischemia-reperfusion model, liver function and inflammatory factors were dynamically varied with reperfusion time in mice, and itaconic acid significantly modified liver function and inflammatory status during this process. NF-κB pathway activity was dynamically varied during hypoxia-reoxygenation, and itaconic acid significantly inhibited the activity of the pathway and significantly suppressed the expression of its downstream inflammation-related proteins.
    Conclusions: Itaconic acid inhibits NF-κB pathway activation and reduces the accumulation of P-P65 in the nucleus. In turn, this reduces NLRP3 and caspase-1 expression of downstream inflammation-related proteins, promotes inflammation regression, and attenuates liver IRI.
    Keywords:  Liver transplantation; ischemia-reperfusion injury (IRI); itaconic acid
    DOI:  https://doi.org/10.21037/atm-22-3388
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