bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2022‒05‒01
nine papers selected by
Avinash N. Mukkala, University of Toronto
  1. Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
  2. Fibroblast growth factor 21, a stress regulator, inhibits Drp1 activation to alleviate skeletal muscle ischemia/reperfusion injury.
  3. Mitochondrial quality control in health and in Parkinson's disease.
  4. Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.
  5. Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis.
  6. Identification of the metabolic remodeling profile in the early-stage of myocardial ischemia and the contributory role of mitochondrion.
  7. L-OPA1 deficiency aggravates necroptosis of alveolar epithelial cells through impairing mitochondrial function during ALI in mice.
  8. Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.
  9. PINK1 mediated mitophagy attenuates early apoptosis of gingival epithelial cells induced by high glucose.
  1. Autophagy. 2022 Apr 26.
    Mitochondrial hitch-hiking of Pink1 mRNA supports axonal mitophagy.
    Angelika B Harbauer, Thomas L Schwarz.
      Mitostasis, the process of mitochondrial maintenance by biogenesis and degradative mechanisms, is challenged by the extreme length of axons. PINK1 (PTEN induced putative kinase 1) is a mitochondrial protein that targets damaged mitochondria for mitophagy. In reconciling the short half-life of PINK1 with the need for mitophagy of damaged axonal mitochondria, we found that axonal mitophagy depends on local translation of the Pink1 mRNA. Using live-cell imaging, we detected co-transport of the Pink1 mRNA on mitochondria in neurons, which is crucial for mitophagy in distal parts of the cell. Here we discuss how the coupling of the transcript of a short-lived mitochondrial protein to the movement of its target organelles contributes to our understanding of mitostasis in neurons.
    Keywords:  Axonal biology; RNA transport; local translation; mitochondria; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2070332
  2. Lab Invest. 2022 Apr 29.
    Fibroblast growth factor 21, a stress regulator, inhibits Drp1 activation to alleviate skeletal muscle ischemia/reperfusion injury.
    Baoxiang Li, Limin Liu.
      Abnormal Drp1 activation and subsequent excessive mitochondrial fission play a critical role in ischemia-reperfusion injury (I/RI). Although fibroblast growth factor 21 (FGF21) protects organs against I/RI and regulates metabolism, which indicates that FGF21 is involved in mitochondria homeostasis, the detailed mechanism remains unclear. Herein, we investigated whether FGF21 had an effect on Drp1 activation during skeletal muscle I/RI. Drp1 phosphorylation and its translocation to mitochondria, as regulated by FGF21, was examined in mouse and C2C12 cell I/RI models. Mice overexpressing FGF21 displayed alleviation of serum index, histological lesions and apoptosis levels. Moreover, FGF21 markedly decreased cyclin-dependent kinase 1 (CDK1) and Drp1 phosphorylation at Ser616, accompanied by reduced accumulation in mitochondria. In parallel in vitro studies, cells with FGF21 knockdown displayed enhanced Drp1 activation, and the reverse effect was found when FGF21 was added. More importantly, FGF21 attenuated mitochondrial fission with linear mitochondria rather than fragmented mitochondria. Furthermore, a CDK1 inhibitor reduced Drp1 activation and mitochondrial fission due to FGF21 knockdown. This study shows that FGF21 inhibits Drp1 activation to protect mitochondria from fission, thereby rescuing cells from I/RI-induced apoptosis. Our findings may provide a new therapeutic approach to ameliorate skeletal muscle I/RI.
    DOI:  https://doi.org/10.1038/s41374-022-00787-7
  3. Physiol Rev. 2022 Apr 25.
    Mitochondrial quality control in health and in Parkinson's disease.
    Mohamed A Eldeeb, Rhalena A Thomas, Mohamed A Ragheb, Armaan Fallahi, Edward A Fon.
      As a central hub for cellular metabolism and intracellular signalling, the mitochondrion is a pivotal organelle, dysfunction of which has been linked to several human diseases including neurodegenerative disorders, and in particular Parkinson's disease. An inherent challenge that mitochondria face is the continuous exposure to diverse stresses which increase their likelihood of dysregulation. In response, eukaryotic cells have evolved sophisticated quality control mechanisms to monitor, identify, repair and/or eliminate abnormal or misfolded proteins within the mitochondrion and/or the dysfunctional mitochondrion itself. Chaperones identify unstable or otherwise abnormal conformations in mitochondrial proteins and can promote their refolding to recover their correct conformation and stability. However, if repair is not possible, the abnormal protein is selectively degraded to prevent potentially damaging interactions with other proteins or its oligomerization into toxic multimeric complexes. The autophagic-lysosomal system and the ubiquitin-proteasome system mediate the selective and targeted degradation of such abnormal or misfolded protein species. Mitophagy (a specific kind of autophagy) mediates the selective elimination of dysfunctional mitochondria, in order to prevent the deleterious effects the dysfunctional organelles within the cell. Despite our increasing understanding of the molecular responses toward dysfunctional mitochondria, many key aspects remain relatively poorly understood. Herein, we review the emerging mechanisms of mitochondrial quality control including quality control strategies coupled to mitochondrial import mechanisms. In addition, we review the molecular mechanisms regulating mitophagy with an emphasis on the regulation of PINK1/PARKIN-mediated mitophagy in cellular physiology and in the context of Parkinson's disease cell biology.
    Keywords:  PINK1/Parkin; Parkinson's disease; mitochondrial quality control; mitophagy; protein quality control
    DOI:  https://doi.org/10.1152/physrev.00041.2021
  4. Nat Immunol. 2022 Apr 28.
    Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.
    Leah K Billingham, Joshua S Stoolman, Karthik Vasan, Arianne E Rodriguez, Taylor A Poor, Marten Szibor, Howard T Jacobs, Colleen R Reczek, Aida Rashidi, Peng Zhang, Jason Miska, Navdeep S Chandel.
      The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.
    DOI:  https://doi.org/10.1038/s41590-022-01185-3
  5. Nat Commun. 2022 Apr 29. 13(1): 2340
    Mitofusin 1 and 2 regulation of mitochondrial DNA content is a critical determinant of glucose homeostasis.
    Vaibhav Sidarala, Jie Zhu, Elena Levi-D'Ancona, Gemma L Pearson, Emma C Reck, Emily M Walker, Brett A Kaufman, Scott A Soleimanpour.
      The dynamin-like GTPases Mitofusin 1 and 2 (Mfn1 and Mfn2) are essential for mitochondrial function, which has been principally attributed to their regulation of fission/fusion dynamics. Here, we report that Mfn1 and 2 are critical for glucose-stimulated insulin secretion (GSIS) primarily through control of mitochondrial DNA (mtDNA) content. Whereas Mfn1 and Mfn2 individually were dispensable for glucose homeostasis, combined Mfn1/2 deletion in β-cells reduced mtDNA content, impaired mitochondrial morphology and networking, and decreased respiratory function, ultimately resulting in severe glucose intolerance. Importantly, gene dosage studies unexpectedly revealed that Mfn1/2 control of glucose homeostasis was dependent on maintenance of mtDNA content, rather than mitochondrial structure. Mfn1/2 maintain mtDNA content by regulating the expression of the crucial mitochondrial transcription factor Tfam, as Tfam overexpression ameliorated the reduction in mtDNA content and GSIS in Mfn1/2-deficient β-cells. Thus, the primary physiologic role of Mfn1 and 2 in β-cells is coupled to the preservation of mtDNA content rather than mitochondrial architecture, and Mfn1 and 2 may be promising targets to overcome mitochondrial dysfunction and restore glucose control in diabetes.
    DOI:  https://doi.org/10.1038/s41467-022-29945-7
  6. Bioengineered. 2022 Apr;13(4): 11106-11121
    Identification of the metabolic remodeling profile in the early-stage of myocardial ischemia and the contributory role of mitochondrion.
    Jun He, Qian Liu, Jie Wang, Fangjing Xu, Yucheng Fan, Ruhua He, Ru Yan, Li Zhu.
      Cardiac remodeling is the primary pathological feature of chronic heart failure. Prompt inhibition of remodeling in acute coronary syndrome has been a standard procedure, but the morbidity and mortality are still high. Exploring the characteristics of ischemia in much earlier stages and identifying its biomarkers are essential for introducing novel mechanisms and therapeutic strategies. Metabolic and structural remodeling of mitochondrion is identified to play key roles in ischemic heart disease. The mitochondrial metabolic features in early ischemia have not previously been described. In the present study, we established a mouse heart in early ischemia and explored the mitochondrial metabolic profile using metabolomics analysis. We also discussed the role of mitochondrion in the global cardiac metabolism. Transmission electron microscopy revealed that mitochondrial structural injury was invoked at 8 minutes post-coronary occlusion. In total, 75 metabolites in myocardium and 26 in mitochondria were screened out. About 23% of the differentiated metabolites in mitochondria overlapped with the differentiated metabolites in myocardium; Total 81% of the perturbed metabolic pathway in mitochondria overlapped with the perturbed pathway in myocardium, and these pathways accounted for 50% of the perturbed pathway in myocardium. Purine metabolism was striking and mechanically important. In conclusion, in the early ischemia, myocardium exacerbated metabolic remodeling. Mitochondrion was a contributor to the myocardial metabolic disorder. Purine metabolism may be a potential biomarker for early ischemia diagnosis. Our study introduced a perspective for prompt identification of ischemia.
    Keywords:  Acute myocardial ischemia; LC-MS/MS; metabolomics; mitochondria; myocardial remodeling
    DOI:  https://doi.org/10.1080/21655979.2022.2068882
  7. J Cell Physiol. 2022 Apr 28.
    L-OPA1 deficiency aggravates necroptosis of alveolar epithelial cells through impairing mitochondrial function during ALI in mice.
    Hui-Ling Jiang, Hui-Hui Yang, Yu-Biao Liu, Chen-Yu Zhang, Wen-Jing Zhong, Xin-Xin Guan, Ling Jin, Jie-Ru Hong, Jin-Tong Yang, Xiao-Hua Tan, Qing Li, Yong Zhou, Cha-Xiang Guan.
      Necroptosis, a recently described form of programmed cell death, is the main way of alveolar epithelial cells (AECs) death in acute lung injury (ALI). While the mechanism of how to trigger necroptosis in AECs during ALI has been rarely evaluated. Long optic atrophy protein 1 (L-OPA1) is a crucial mitochondrial inner membrane fusion protein, and its deficiency impairs mitochondrial function. This study aimed to investigate the role of L-OPA1 deficiency-mediated mitochondrial dysfunction in AECs necroptosis. We comprehensively investigated the detailed contribution and molecular mechanism of L-OPA1 deficiency in AECs necroptosis by inhibiting or activating L-OPA1. Firstly, our data showed that L-OPA1 expression was down-regulated in the lungs and AECs under the lipopolysaccharide (LPS) challenge. Furthermore, inhibition of L-OPA1 aggravated the pathological injury, inflammatory response, and necroptosis in the lungs of LPS-induced ALI mice. In vitro, inhibition of L-OPA1 induced necroptosis of AECs, while activation of L-OPA1 alleviated necroptosis of AECs under the LPS challenge. Mechanistically, inhibition of L-OPA1 aggravated necroptosis of AECs by inducing mitochondrial fragmentation and reducing mitochondrial membrane potential. While activation of L-OPA1 had the opposite effects. In summary, these findings indicate for the first time that L-OPA1 deficiency mediates mitochondrial fragmentation, induces necroptosis of AECs, and exacerbates ALI in mice. This article is protected by copyright. All rights reserved.
    Keywords:  L-OPA1; acute lung injury; alveolar epithelial cells; mitochondrial fragmentation; necroptosis
    DOI:  https://doi.org/10.1002/jcp.30766
  8. Nat Chem Biol. 2022 May;18(5): 461-469
    Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.
    Michael P Murphy, Edward T Chouchani.
      Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.
    DOI:  https://doi.org/10.1038/s41589-022-01004-8
  9. BMC Oral Health. 2022 Apr 26. 22(1): 144
    PINK1 mediated mitophagy attenuates early apoptosis of gingival epithelial cells induced by high glucose.
    Chunhui Zhu, Ying Zhao, Dandan Pei, Zhongbo Liu, Jin Liu, Ye Li, Shuchen Yu, Lingyan Ma, Junyi Sun, Ang Li.
      BACKGROUND: Oxidative stress mediated by hyperglycemia damages cell-reparative processes such as mitophagy. Down-regulation of mitophagy is considered to be a susceptible factor for diabetes mellitus (DM) and its complications. However, the role of mitophagy in DM-associated periodontitis has not been fully elucidated. Apoptosis of human gingival epithelial cells (hGECs) is one of the representative events of DM-associated periodontitis. Thus, this study aimed to investigate PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy activated in the process of high glucose (HG)-induced hGECs apoptosis.METHODS: For dose-response studies, hGECs were incubated in different concentrations of glucose (5.5, 15, 25, and 50 mmol/L) for 48 h. Then, hGECs were challenged with 25 mmol/L glucose for 12 h and 48 h, respectively. Apoptosis was detected by TdT-mediated dUTP nick end labeling (TUNEL), caspase 9 and mitochondrial membrane potential (MMP). Subsequently, autophagy was evaluated by estimating P62, LC3 II mRNA levels, LC3 fluorescent puncta and LC3-II/I ratio. Meanwhile, the involvement of PINK1-mediated mitophagy was assessed by qRT-PCR, western blotting and immunofluorescence. Finally, hGECs were transfected with shPINK1 and analyzed by MMP, caspase 9 and annexin V-FITC apoptosis.
    RESULTS: The number of TUNEL-positive cells and caspase 9 protein were significantly increased in cells challenged with HG (25 mmol/L) for 48 h (HG 48 h). MMP was impaired both at HG 12 h and HG 48 h, but the degree of depolarization was more serious at HG 48 h. The autophagy improved as the amount of LC3 II increased and p62 decreased in HG 12 h. During this process, HG 12 h treatment induced PINK1-mediated mitophagy. PINK1 silencing with HG 12 h resulted in MMP depolarization and cell apoptosis.
    CONCLUSIONS: These results suggested that loss of the PINK1 gene may cause mitochondrial dysfunction and increase sensitivity to HG-induced apoptosis of hGECs at the early stage. PINK1 mediated mitophagy attenuates early apoptosis of gingival epithelial cells induced by high glucose.
    Keywords:  Apoptosis; Diabetes mellitus; Human gingival epithelial cells; Mitophagy; PINK1; Periodontitis; Short-term high glucose
    DOI:  https://doi.org/10.1186/s12903-022-02167-5
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