bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2023‒09‒17
twelve papers selected by
Gavin McStay, Liverpool John Moores University
  1. Mitochondrial degradation: Mitophagy and beyond.
  2. Prefoldin 2 contributes to mitochondrial morphology and function.
  3. Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury.
  4. PA2G4/EBP1 ubiquitination by PRKN/PARKIN promotes mitophagy protecting neuron death in cerebral ischemia.
  5. Parkin-mediated mitophagy protects against aluminum trichloride-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway.
  6. The Role of Parkin in Rat Pancreatic Beta Cells Fate.
  7. Alternative to lysosomal degradation: mitochondrial removal via EVs.
  8. Correction to: Mitophagy activation repairs Leber's hereditary optic neuropathy-associated mitochondrial dysfunction and improves cell survival.
  9. Insulin-like growth factor binding protein-3 mediates hyperosmolar stress-induced mitophagy through the mechanistic target of rapamycin.
  10. PKR activation in mitochondrial unfolded protein response-mitochondrial dsRNA might do the trick.
  11. Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.
  12. Early steps in the biogenesis of mitochondrially encoded oxidative phosphorylation subunits.
  1. Mol Cell. 2023 Sep 07. pii: S1097-2765(23)00656-1. [Epub ahead of print]
    Mitochondrial degradation: Mitophagy and beyond.
    Louise Uoselis, Thanh Ngoc Nguyen, Michael Lazarou.
      Mitochondria are central hubs of cellular metabolism that also play key roles in signaling and disease. It is therefore fundamentally important that mitochondrial quality and activity are tightly regulated. Mitochondrial degradation pathways contribute to quality control of mitochondrial networks and can also regulate the metabolic profile of mitochondria to ensure cellular homeostasis. Here, we cover the many and varied ways in which cells degrade or remove their unwanted mitochondria, ranging from mitophagy to mitochondrial extrusion. The molecular signals driving these varied pathways are discussed, including the cellular and physiological contexts under which the different degradation pathways are engaged.
    Keywords:  MDV; PINK1; Parkin; degradation; mitochondria; mitochondrial quality control; mitophagy; proteasome; selective autophagy; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.08.021
  2. BMC Biol. 2023 09 12. 21(1): 193
    Prefoldin 2 contributes to mitochondrial morphology and function.
    Ismail Tahmaz, Somayeh Shahmoradi Ghahe, Monika Stasiak, Kamila P Liput, Katarzyna Jonak, Ulrike Topf.
      BACKGROUND: Prefoldin is an evolutionarily conserved co-chaperone of the tailless complex polypeptide 1 ring complex (TRiC)/chaperonin containing tailless complex 1 (CCT). The prefoldin complex consists of six subunits that are known to transfer newly produced cytoskeletal proteins to TRiC/CCT for folding polypeptides. Prefoldin function was recently linked to the maintenance of protein homeostasis, suggesting a more general function of the co-chaperone during cellular stress conditions. Prefoldin acts in an adenosine triphosphate (ATP)-independent manner, making it a suitable candidate to operate during stress conditions, such as mitochondrial dysfunction. Mitochondrial function depends on the production of mitochondrial proteins in the cytosol. Mechanisms that sustain cytosolic protein homeostasis are vital for the quality control of proteins destined for the organelle and such mechanisms among others include chaperones.RESULTS: We analyzed consequences of the loss of prefoldin subunits on the cell proliferation and survival of Saccharomyces cerevisiae upon exposure to various cellular stress conditions. We found that prefoldin subunits support cell growth under heat stress. Moreover, prefoldin facilitates the growth of cells under respiratory growth conditions. We showed that mitochondrial morphology and abundance of some respiratory chain complexes was supported by the prefoldin 2 (Pfd2/Gim4) subunit. We also found that Pfd2 interacts with Tom70, a receptor of mitochondrial precursor proteins that are targeted into mitochondria.
    CONCLUSIONS: Our findings link the cytosolic prefoldin complex to mitochondrial function. Loss of the prefoldin complex subunit Pfd2 results in adaptive cellular responses on the proteome level under physiological conditions suggesting a continuous need of Pfd2 for maintenance of cellular homeostasis. Within this framework, Pfd2 might support mitochondrial function directly as part of the cytosolic quality control system of mitochondrial proteins or indirectly as a component of the protein homeostasis network.
    Keywords:  Chaperone; Mitochondria; Pfd2/Gim4; Prefoldin; Proteostasis; Tom70
    DOI:  https://doi.org/10.1186/s12915-023-01695-y
  3. Int J Biol Sci. 2023 ;19(13): 4327-4339
    Sirtuin-3 activates the mitochondrial unfolded protein response and reduces cerebral ischemia/reperfusion injury.
    Xie Xiaowei, Xu Qian, Zhou Dingzhou.
      Sirtuin-3 (Sirt3) deacetylates several mitochondrial proteins implicated into cerebral ischemia/reperfusion (I/R) injury. The mitochondrial unfolded protein response (UPRmt) favors mitochondrial proteostasis during various stressors. Here, we used Sirt3 transgenic mice and a transient middle cerebral artery occlusion model to evaluate the molecular basis of Sirt3 on the UPRmt during brain post-ischemic dysfunction. The present study illustrated that Sirt3 abundance was suppressed in the brain after brain ischemic abnormalities. Overexpression of Sirt3 in vivo suppressed the infarction size and attenuated neuroinflammation after brain I/R injury. Sirt3 overexpression restored neural viability by reducing mitochondrial ROS synthesis, maintaining the mitochondrial potential and improving mitochondrial adenosine triphosphate synthesis. Sirt3 overexpression protected neuronal mitochondria against brain post-ischemic malfunction via eliciting the UPRmt by the forkhead box O3 (Foxo3)/sphingosine kinase 1 (Sphk1) pathway. Inhibiting either the UPRmt or the Foxo3/Sphk1 pathway relieved the favorable influence of Sirt3 on neural function and mitochondrial behavior. In contrast, Sphk1 overexpression was sufficient to reduce the infarction size, attenuate neuroinflammation, sustain neuronal viability and prevent mitochondrial abnormalities during brain post-ischemia dysfunction. Thus, the UPRmt protects neural viability and mitochondrial homeostasis, and the Sirt3/Foxo3/Sphk1 pathway is a promosing therapeutic candidate for ischemic stroke.
    Keywords:  Foxo3; Sirt3; Sphk1; UPRmt; cerebral I/R injury; mitochondria
    DOI:  https://doi.org/10.7150/ijbs.86614
  4. Autophagy. 2023 Sep 15.
    PA2G4/EBP1 ubiquitination by PRKN/PARKIN promotes mitophagy protecting neuron death in cerebral ischemia.
    Inwoo Hwang, Byeong-Seong Kim, Ho Yun Lee, Sung-Woo Cho, Seung Eun Lee, Jee-Yin Ahn.
      Cerebral ischemia induces massive mitochondrial damage, leading to neuronal death. The elimination of damaged mitochondria via mitophagy is critical for neuroprotection. Here we show that the level of PA2G4/EBP1 (proliferation-associated 2G4) was notably increased early during transient middle cerebral artery occlusion and prevented neuronal death by eliciting cerebral ischemia-reperfusion (IR)-induced mitophagy. Neuron-specific knockout of Pa2g4 increased infarct volume and aggravated neuron loss with impaired mitophagy and was rescued by introduction of adeno-associated virus serotype 2 expressing PA2G4/EBP1. We determined that PA2G4/EBP1 is ubiquitinated on lysine 376 by PRKN/PARKIN on the damaged mitochondria and interacts with receptor protein SQSTM1/p62 for mitophagy induction. Thus, our study suggests that PA2G4/EBP1 ubiquitination following cerebral IR-injury promotes mitophagy induction, which may be implicated in neuroprotection.
    Keywords:  Ischemia; PA2G4/EBP1; PRKN/PARKIN; SQSTM1/p62; mitophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2259215
  5. Ecotoxicol Environ Saf. 2023 Sep 11. pii: S0147-6513(23)00963-6. [Epub ahead of print]264 115459
    Parkin-mediated mitophagy protects against aluminum trichloride-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway.
    Siming Huo, Xuliang Zhang, Jinyu Xu, Jian Zhang, Jiayu Du, Bo Li, Miao Song, Bing Shao, Yanfei Li, Feibo Xu.
      Aluminum is a neurotoxic food contaminant. Aluminum trichloride (AlCl3) causes hippocampal mitochondrial damage, leading to hippocampal injury. Damaged mitochondria can release mitochondrial reactive oxygen species (mtROS) and activate nucleotide-binding oligomerization domain-like receptor-containing 3 (NLRP3) inflammasomes and apoptosis. E3 ubiquitin ligase PARK2 (Parkin)-mediated mitophagy can attenuate mitochondrial damage. However, the role of mitophagy in AlCl3-induced mice hippocampal damage and its regulatory mechanism remain elusive. First, C57BL/6 N mice were treated with 0, 44.825, 89.65, and 179.3 mg/kg body weight AlCl3 drinking water for 90 d. Apoptosis, NLRP3-inflammasome activation and mitochondrial damage were increased in AlCl3-induced hippocampal damage. In addition, Parkin-mediated mitophagy peaked in the middle-dose group and was slightly attenuated in the high-dose group. Subsequently, we used wild-type and Parkin knockout (Parkin-/-) mice to investigate the AlCl3-induced hippocampal damage. The results showed that Parkin-/- inhibited mitophagy, and aggravated AlCl3-induced mitochondrial damage, NLRP3-inflammasome activation, apoptosis and hippocampal damage. Finally, we administered MitoQ (mtROS inhibitor) and MCC950 (NLRP3 inhibitor) to AlCl3-treated Parkin-/- mice to investigate the mechanism of Parkin-mediated mitophagy. The results showed that inhibition of mtROS and NLRP3 attenuated hippocampal NLRP3-inflammasome activation, apoptosis, and damage in AlCl3-treated Parkin-/- mice. These findings indicate that Parkin-mediated mitophagy protects against AlCl3-induced hippocampal apoptosis in mice via the mtROS-NLRP3 pathway.
    Keywords:  Aluminum; Mitochondrial reactive oxygen species; Mitophagy; NLRP3-inflammasome; Neurodegenerative diseases; Parkin
    DOI:  https://doi.org/10.1016/j.ecoenv.2023.115459
  6. Cell Mol Biol (Noisy-le-grand). 2023 Aug 31. 69(8): 57-67
    The Role of Parkin in Rat Pancreatic Beta Cells Fate.
    Hasibe Verdi, Hatice Pinar Baysan Cebi, Yaprak Yilmaz Yalcin, Tulin Ozkan, Mehtap Akcil Ok, Asuman Sunguroglu, Fatma Belgin Atac.
      Parkin is a member of the mitochondrial quality control system that plays a major role in mitophagy. Although the loss of function mutations in the Parkin gene has been associated with the Familial Parkinson's phenotype, research in recent years points out that Parkin's function is not limited to neurodegenerative diseases. Parkin's function impressing key cellular quality control mechanisms, including the ubiquitin-proteasome and autophagy-lysosome systems, makes it an important player in the maintenance of cellular homeostasis. In this study, we investigated whether Parkin affects cell viability and ER stress responses under lipotoxic conditions in INS-1E cells. Our results may suggest that silencing Parkin may affect autophagy in addition to apoptosis.  We also showed that Parkin may have a protective effect against lipo-toxic effects in INS-1E cells. Consistent with previous studies, we observed that stress responses were different for high and low palmitic acid doses. The Parkin being inhibited under high-dose PA treatment and active under low-dose PA treatment indicate that regulation of stress responses is controlled by environmental conditions. Our preliminary findings may suggest that in low lipotoxic conditions, Parkin affects the ER stress response by modulating Chop activity and Ca2+ release from the ER to the cytoplasm.
    DOI:  https://doi.org/10.14715/cmb/2023.69.8.9
  7. Nat Rev Mol Cell Biol. 2023 Sep 11.
    Alternative to lysosomal degradation: mitochondrial removal via EVs.
    Paulina Strzyz.
      
    DOI:  https://doi.org/10.1038/s41580-023-00660-5
  8. Hum Mol Genet. 2023 Sep 12. pii: ddad148. [Epub ahead of print]
    Correction to: Mitophagy activation repairs Leber's hereditary optic neuropathy-associated mitochondrial dysfunction and improves cell survival.
      
    DOI:  https://doi.org/10.1093/hmg/ddad148
  9. J Biol Chem. 2023 Sep 08. pii: S0021-9258(23)02267-6. [Epub ahead of print] 105239
    Insulin-like growth factor binding protein-3 mediates hyperosmolar stress-induced mitophagy through the mechanistic target of rapamycin.
    Whitney Stuard Sambhariya, Ian J Trautmann, Danielle M Robertson.
      Hyperosmolarity of the ocular surface triggers inflammation and pathological damage in dry eye disease (DED). In addition to a reduction in quality of life, DED causes vision loss and when severe, blindness. Mitochondrial dysfunction occurs as a consequence of hyperosmolar stress. We have previously reported on a role for the insulin-like growth factor binding protein-3 (IGFBP-3) in the regulation of mitochondrial ultrastructure and metabolism in mucosal surface epithelial cells; however, this appears to be context specific. Due to the finding that IGFBP-3 expression is decreased in response to hyperosmolar stress in vitro and in an animal model of DED, we next sought to determine whether the hyperosmolar stress-mediated decrease in IGFBP-3 alters mitophagy, a key mitochondrial quality control mechanism. Here we show that hyperosmolar stress induces mitophagy through differential regulation of BNIP3L/NIX and PINK1-mediated pathways. In corneal epithelial cells, this was independent of p62. The addition of exogenous IGFBP-3 abrogated the increase in mitophagy. This occurred through regulation of mTOR, highlighting the existence of a new IGFBP-3-mTOR signaling pathway. Together, these findings support a novel role for IGFBP-3 in mediating mitochondrial quality control in DED and have broad implications for epithelial tissues subject to hyperosmolar stress and other mitochondrial diseases.
    DOI:  https://doi.org/10.1016/j.jbc.2023.105239
  10. Front Cell Dev Biol. 2023 ;11 1270341
    PKR activation in mitochondrial unfolded protein response-mitochondrial dsRNA might do the trick.
    Eva Rath.
      
    Keywords:  double-stranded RNA-activated protein kinase; doublestranded RNA; inflammatory bowel diseases; integrated stress response; mitochondria; mitochondrial unfolded protein response; proteostasis; stress signaling
    DOI:  https://doi.org/10.3389/fcell.2023.1270341
  11. Redox Biol. 2023 Sep 07. pii: S2213-2317(23)00272-0. [Epub ahead of print]67 102871
    Mesenchymal stem cell attenuates spinal cord injury by inhibiting mitochondrial quality control-associated neuronal ferroptosis.
    Senyu Yao, Mao Pang, Yanheng Wang, Xiaokang Wang, Yaobang Lin, Yanyan Lv, Ziqi Xie, Jianfeng Hou, Cong Du, Yuan Qiu, Yuanjun Guan, Bin Liu, Jiancheng Wang, Andy Peng Xiang, Limin Rong.
      Ferroptosis is a newly discovered form of iron-dependent oxidative cell death and drives the loss of neurons in spinal cord injury (SCI). Mitochondrial damage is a critical contributor to neuronal death, while mitochondrial quality control (MQC) is an essential process for maintaining mitochondrial homeostasis to promote neuronal survival. However, the role of MQC in neuronal ferroptosis has not been clearly elucidated. Here, we further demonstrate that neurons primarily suffer from ferroptosis in SCI at the single-cell RNA sequencing level. Mechanistically, disordered MQC aggravates ferroptosis through excessive mitochondrial fission and mitophagy. Furthermore, mesenchymal stem cells (MSCs)-mediated mitochondrial transfer restores neuronal mitochondria pool and inhibits ferroptosis through mitochondrial fusion by intercellular tunneling nanotubes. Collectively, these results not only suggest that neuronal ferroptosis is regulated in an MQC-dependent manner, but also fulfill the molecular mechanism by which MSCs attenuate neuronal ferroptosis at the subcellular organelle level. More importantly, it provides a promising clinical translation strategy based on stem cell-mediated mitochondrial therapy for mitochondria-related central nervous system disorders.
    Keywords:  Intercellular mitochondrial transfer; Mesenchymal stem cells; Mitochondrial quality control; Neuronal ferroptosis; Spinal cord injury
    DOI:  https://doi.org/10.1016/j.redox.2023.102871
  12. IUBMB Life. 2023 Sep 15.
    Early steps in the biogenesis of mitochondrially encoded oxidative phosphorylation subunits.
    Sung-Jun Jung, Sagar Sridhara, Martin Ott.
      The complexes mediating oxidative phosphorylation (OXPHOS) in the inner mitochondrial membrane consist of proteins encoded in the nuclear or the mitochondrial DNA. The mitochondrially encoded membrane proteins (mito-MPs) represent the catalytic core of these complexes and follow complicated pathways for biogenesis. Owing to their overall hydrophobicity, mito-MPs are co-translationally inserted into the inner membrane by the Oxa1 insertase. After insertion, OXPHOS biogenesis factors mediate the assembly of mito-MPs into complexes and participate in the regulation of mitochondrial translation, while protein quality control factors recognize and degrade faulty or excess proteins. This review summarizes the current understanding of these early steps occurring during the assembly of mito-MPs by concentrating on results obtained in the model organism baker's yeast.
    Keywords:  eukaryotic gene expression; mitochondria; protein folding; protein synthesis
    DOI:  https://doi.org/10.1002/iub.2784
This page is being maintained by Thomas Krichel. It was last updated on 2024‒07‒26 at 16:53.