bims-mitlys Biomed News
on Mitochondria and Lysosomes
Issue of 2021–07–25
seven papers selected by
Nicoletta Plotegher, University of Padova
  1. SAMM50 is a receptor for basal piecemeal mitophagy and acts with SQSTM1/p62 in OXPHOS-induced mitophagy.
  2. Mitochondrial Quality Control in Cerebral Ischemia-Reperfusion Injury.
  3. CVB3-Mediated Mitophagy Plays an Important Role in Viral Replication via Abrogation of Interferon Pathways.
  4. ER - lysosome contacts at a pre-axonal region regulate axonal lysosome availability.
  5. Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets.
  6. The mitophagy receptor FUN14 domain-containing 1 (FUNDC1): A promising biomarker and potential therapeutic target of human diseases.
  7. Deubiquitinating enzyme USP30 negatively regulates mitophagy and accelerates myocardial cell senescence through antagonism of Parkin.
  1. Autophagy. 2021 Jul 18. 1-3
    SAMM50 is a receptor for basal piecemeal mitophagy and acts with SQSTM1/p62 in OXPHOS-induced mitophagy.
    Yakubu Princely Abudu, Stephane Mouilleron, Sharon A Tooze, Trond Lamark, Terje Johansen.
      Mitophagy, the clearance of surplus or damaged mitochondria or mitochondrial parts by autophagy, is important for maintenance of cellular homeostasis. Whereas knowledge on programmed and stress-induced mitophagy is increasing, much less is known about mechanisms of basal mitophagy. Recently, we identified SAMM50 (SAMM50 sorting and assembly machinery component) as a receptor for piecemeal degradation of components of the sorting and assembly machinery (SAM) complex and mitochondrial contact site and cristae organizing system (MICOS) complexes. SAMM50 interacts directly with Atg8-family proteins through a canonical LIR motif and with SQSTM1/p62 to mediate basal piecemeal mitophagy. During a metabolic switch to oxidative phosphorylation (OXPHOS), SAMM50 cooperates with SQSTM1 to mediate efficient piecemeal mitophagy.
    Keywords:  Atg8; MICOS; OXPHOS; SAMM50; SQSTM1; basal; metabolic switch; p62; piecemeal mitophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1953846
  2. Mol Neurobiol. 2021 Jul 18.
    Mitochondrial Quality Control in Cerebral Ischemia-Reperfusion Injury.
    Mimi Wu, Xiaoping Gu, Zhengliang Ma.
      Ischemic stroke is one of the leading causes of death and also a major cause of adult disability worldwide. Revascularization via reperfusion therapy is currently a standard clinical procedure for patients with ischemic stroke. Although the restoration of blood flow (reperfusion) is critical for the salvage of ischemic tissue, reperfusion can also, paradoxically, exacerbate neuronal damage through a series of cellular alterations. Among the various theories postulated for ischemia/reperfusion (I/R) injury, including the burst generation of reactive oxygen species (ROS), activation of autophagy, and release of apoptotic factors, mitochondrial dysfunction has been proposed to play an essential role in mediating these pathophysiological processes. Therefore, strict regulation of the quality and quantity of mitochondria via mitochondrial quality control is of great importance to avoid the pathological effects of impaired mitochondria on neurons. Furthermore, timely elimination of dysfunctional mitochondria via mitophagy is also crucial to maintain a healthy mitochondrial network, whereas intensive or excessive mitophagy could exacerbate cerebral I/R injury. This review will provide a comprehensive overview of the effect of mitochondrial quality control on cerebral I/R injury and introduce recent advances in the understanding of the possible signaling pathways of mitophagy and potential factors responsible for the double-edged roles of mitophagy in the pathological processes of cerebral I/R injury.
    Keywords:  Cerebral ischemia; Mitochondrial; Mitochondrial quality control; Mitophagy; Reperfusion
    DOI:  https://doi.org/10.1007/s12035-021-02494-8
  3. Front Cell Infect Microbiol. 2021 ;11 704494
    CVB3-Mediated Mitophagy Plays an Important Role in Viral Replication via Abrogation of Interferon Pathways.
    Soo-Jin Oh, Byung-Kwan Lim, Jeanho Yun, Ok Sarah Shin.
      Coxsackievirus B3 (CVB3) is a common enterovirus that causes systemic inflammatory diseases, such as myocarditis, meningitis, and encephalitis. CVB3 has been demonstrated to subvert host cellular responses via autophagy to support viral replication in neural stem cells. Mitophagy, a specialized form of autophagy, contributes to mitochondrial quality control via degrading damaged mitochondria. Here, we show that CVB3 infection induces mitophagy in human neural progenitor cells, HeLa and H9C2 cardiomyocytes. In particular, CVB3 infection triggers mitochondrial fragmentation, loss of mitochondrial membrane potential, and Parkin/LC3 translocation to the mitochondria. Rapamycin or carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment led to increased CVB3 RNA copy number in a dose-dependent manner, suggesting enhanced viral replication via autophagy/mitophagy activation, whereas knockdown of PTEN-induced putative kinase protein 1(PINK1) led to impaired mitophagy and subsequent reduction in viral replication. Furthermore, CCCP treatment inhibits the interaction between mitochondrial antiviral signaling protein (MAVS) and TANK-binding kinase 1(TBK1), thus contributing to the abrogation of type I and III interferon (IFN) production, suggesting that mitophagy is essential for the inhibition of interferon signaling. Our findings suggest that CVB3-mediated mitophagy suppresses IFN pathways by promoting fragmentation and subsequent sequestration of mitochondria by autophagosomes.
    Keywords:  Coxsackievirus B3 virus; interferon; mitochondrial dynamics; mitophagy; neural progenitor cells and stem cells
    DOI:  https://doi.org/10.3389/fcimb.2021.704494
  4. Nat Commun. 2021 Jul 23. 12(1): 4493
    ER - lysosome contacts at a pre-axonal region regulate axonal lysosome availability.
    Nazmiye Özkan, Max Koppers, Inge van Soest, Alexandra van Harten, Daphne Jurriens, Nalan Liv, Judith Klumperman, Lukas C Kapitein, Casper C Hoogenraad, Ginny G Farías.
      Neuronal function relies on careful coordination of organelle organization and transport. Kinesin-1 mediates transport of the endoplasmic reticulum (ER) and lysosomes into the axon and it is increasingly recognized that contacts between the ER and lysosomes influence organelle organization. However, it is unclear how organelle organization, inter-organelle communication and transport are linked and how this contributes to local organelle availability in neurons. Here, we show that somatic ER tubules are required for proper lysosome transport into the axon. Somatic ER tubule disruption causes accumulation of enlarged and less motile lysosomes at the soma. ER tubules regulate lysosome size and axonal translocation by promoting lysosome homo-fission. ER tubule - lysosome contacts often occur at a somatic pre-axonal region, where the kinesin-1-binding ER-protein P180 binds microtubules to promote kinesin-1-powered lysosome fission and subsequent axonal translocation. We propose that ER tubule - lysosome contacts at a pre-axonal region finely orchestrate axonal lysosome availability for proper neuronal function.
    DOI:  https://doi.org/10.1038/s41467-021-24713-5
  5. Front Physiol. 2021 ;12 700585
    Molecular Perspectives of Mitophagy in Myocardial Stress: Pathophysiology and Therapeutic Targets.
    Haizhe Ji, Dan Wu, O'Maley Kimberlee, Ruibing Li, Geng Qian.
      A variety of complex risk factors and pathological mechanisms contribute to myocardial stress, which ultimately promotes the development of cardiovascular diseases, including acute cardiac insufficiency, myocardial ischemia, myocardial infarction, high-glycemic myocardial injury, and acute alcoholic cardiotoxicity. Myocardial stress is characterized by abnormal metabolism, excessive reactive oxygen species production, an insufficient energy supply, endoplasmic reticulum stress, mitochondrial damage, and apoptosis. Mitochondria, the main organelles contributing to the energy supply of cardiomyocytes, are key determinants of cell survival and death. Mitophagy is important for cardiomyocyte function and metabolism because it removes damaged and aged mitochondria in a timely manner, thereby maintaining the proper number of normal mitochondria. In this review, we first introduce the general characteristics and regulatory mechanisms of mitophagy. We then describe the three classic mitophagy regulatory pathways and their involvement in myocardial stress. Finally, we discuss the two completely opposite effects of mitophagy on the fate of cardiomyocytes. Our summary of the molecular pathways underlying mitophagy in myocardial stress may provide therapeutic targets for myocardial protection interventions.
    Keywords:  BCL2 interacting protein 3; FUN14 domain-containing 1; Nix; PTEN-induced putative kinase protein-1/Parkin; cardiovascular stress; mitophagy
    DOI:  https://doi.org/10.3389/fphys.2021.700585
  6. Genes Dis. 2021 Sep;8(5): 640-654
    The mitophagy receptor FUN14 domain-containing 1 (FUNDC1): A promising biomarker and potential therapeutic target of human diseases.
    Weilin Zhang.
      Mitochondrial autophagy (mitophagy) is the selective clearance of damaged or incomplete mitochondria by autophagy, which is critical for the functional integrity of the entire mitochondrial network and cell survival. Because dysfunction of mitophagy is closely related to many diseases, it is important to study the specific molecular mechanism and pathophysiological significance of mitophagy. FUN14 domain-containing 1 (FUNDC1) is a newly identified mitochondrial outer membrane protein that induces receptor-mediated mitophagy by its interaction with LC3 during hypoxia. The expression, phosphorylation, regulation and significance of FUNDC1 are reviewed in the context of a large number of pathophysiological conditions. Emerging evidence has demonstrated that levels and phosphorylation states of FUNDC1 are closely related to occurrence, progression and prognosis of various diseases including heart diseases and cancers, indicating that FUNDC1 may serve as a promising biomarker and potential therapeutic target.
    Keywords:  Autophagy; Biomarker; FUNDC1; Heart diseases; Hypoxia; Mitochondria; Mitochondrial ROS; Platelets
    DOI:  https://doi.org/10.1016/j.gendis.2020.08.011
  7. Cell Death Discov. 2021 Jul 21. 7(1): 187
    Deubiquitinating enzyme USP30 negatively regulates mitophagy and accelerates myocardial cell senescence through antagonism of Parkin.
    Wei Pan, Yaowen Wang, Xinyu Bai, Yuehui Yin, Limeng Dai, Hong Zhou, Qin Wu, Yan Wang.
      Cell senescence is associated with age-related pathological changes. Increasing evidence has revealed that mitophagy can selectively remove dysfunctional mitochondria. Overexpression of ubiquitin-specific protease 30 (USP30) has been documented to influence mitophagy and deubiquitination of mitochondrial Parkin substrates. This study was conducted to evaluate the roles of USP30 and Parkin in myocardial cell senescence and mitophagy. Initially, myocardial cells were isolated from neonatal SD rats and subjected to D-gal treatment to induce cell senescence, after which the effects of D-gal on mitochondria damage, ROS production, cell senescence, and mitophagy were assessed. The myocardial cells were infected with lentiviruses bearing overexpression plasmids or shRNA targeting Parkin or USP30 to elucidate the effects of Parkin and USP30 on D-gal-induced mitophagy damage and cell senescence. Finally, aging was induced in rats by subcutaneous injection of D-gal to determine the role of Parkin and USP30 on cell senescence in vivo. D-gal was found to trigger mitochondria damage, ROS production, and cell senescence in myocardial cells. The overexpression of Parkin or silencing of USP30 reduced D-gal-induced mitochondrial damage and relieved D-gal-induced myocardial cell senescence. Moreover, the in vivo experiments validated that either elevation of Parkin or silencing USP30 could alleviate D-gal-induced myocardial cell senescence in rats. Silencing USP30 alleviates D-gal-induced mitochondrial damage and consequently suppresses myocardial cell senescence by activating Parkin. Our study highlights the potential of USP30 as a novel target against myocardial cell senescence.
    DOI:  https://doi.org/10.1038/s41420-021-00546-5
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