bims-auttor Biomed News
on Autophagy and mTOR
Issue of 2020‒03‒29
seventeen papers selected by
Viktor Korolchuk, Newcastle University
  1. Autophagy and mTOR signaling during intervertebral disc aging and degeneration.
  2. A triterpenoid Nrf2 activator, RS9, promotes LC3-associated phagocytosis of photoreceptor outer segments in a p62-independent manner.
  3. Protein Aggregation and Dysfunction of Autophagy-Lysosomal Pathway: A Vicious Cycle in Lysosomal Storage Diseases.
  4. Ibudilast enhances the clearance of SOD1 and TDP-43 aggregates through TFEB-mediated autophagy and lysosomal biogenesis: The new molecular mechanism of ibudilast and its implication for neuroprotective therapy.
  5. Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.
  6. Autophagosomes are formed at a distinct cellular structure.
  7. AMPK activation induces mitophagy and promotes mitochondrial fission while activating TBK1 in a PINK1-Parkin independent manner.
  8. Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons.
  9. Inter-organelle lipid transfer: a channel model for Vps13 and chorein-N motif proteins.
  10. Lysine-specific demethylase 3A is important for autophagic occurrence.
  11. Cell Senescence, DNA Damage and Metabolism.
  12. ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging.
  13. Dihydrotanshinone I Increase Amyloid-β Clearance and Decrease Tau Phosphorylation via Enhancing Autophagy.
  14. SIRT2 Affects Primary Cilia Formation by Regulating mTOR Signaling in Retinal Pigmented Epithelial Cells.
  15. Verapamil extends lifespan in Caenorhabditis elegans by inhibiting calcineurin activity and promoting autophagy.
  16. Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease.
  17. Mitophagy in Cardiovascular Diseases.
  1. JOR Spine. 2020 Mar;3(1): e1082
    Autophagy and mTOR signaling during intervertebral disc aging and degeneration.
    Takashi Yurube, Masaaki Ito, Yuji Kakiuchi, Ryosuke Kuroda, Kenichiro Kakutani.
      Degenerative disc disease is a highly prevalent, global health problem that represents the primary cause of back pain and is associated with neurological disorders, including radiculopathy, myelopathy, and paralysis, resulting in worker disability and socioeconomic burdens. The intervertebral disc is the largest avascular organ in the body, and degeneration is suspected to be linked to nutritional deficiencies. Autophagy, the process through which cells self-digest and recycle damaged components, is an important cell survival mechanism under stress conditions, especially nutrient deprivation. Autophagy is negatively controlled by the mammalian target of rapamycin (mTOR) signaling pathway. mTOR is a serine/threonine kinase that detects nutrient availability to trigger the activation of cell growth and protein synthesis pathways. Thus, resident disc cells may utilize autophagy and mTOR signaling to cope with harsh low-nutrient conditions, such as low glucose, low oxygen, and low pH. We performed rabbit and human disc cell and tissue studies to elucidate the involvement and roles played by autophagy and mTOR signaling in the intervertebral disc. In vitro serum and nutrient deprivation studies resulted in decreased disc cell proliferation and metabolic activity and increased apoptosis and senescence, in addition to increased autophagy. The selective RNA interference-mediated and pharmacological inhibition of mTOR complex 1 (mTORC1) was protective against inflammation-induced disc cellular apoptosis, senescence, and extracellular matrix catabolism, through the induction of autophagy and the activation of the Akt-signaling network. Although temsirolimus, a rapamycin derivative with improved water solubility, was the most effective mTORC1 inhibitor tested, dual mTOR inhibitors, capable of blocking multiple mTOR complexes, did not rescue disc cells. In vivo, high levels of mTOR-signaling molecule expression and phosphorylation were observed in human intermediately degenerated discs and decreased with age. A mechanistic understanding of autophagy and mTOR signaling can provide a basis for the development of biological therapies to treat degenerative disc disease.
    Keywords:  aging; autophagy; disc degeneration; intervertebral disc; mTOR signaling; spine
    DOI:  https://doi.org/10.1002/jsp2.1082
  2. Free Radic Biol Med. 2020 Mar 23. pii: S0891-5849(20)30456-1. [Epub ahead of print]
    A triterpenoid Nrf2 activator, RS9, promotes LC3-associated phagocytosis of photoreceptor outer segments in a p62-independent manner.
    Yuichi Saito, Tomohiro Yako, Wataru Otsu, Shinsuke Nakamura, Yuki Inoue, Aomi Muramatsu, Yasuhiro Nakagami, Masamitsu Shimazawa, Hideaki Hara.
      Daily phagocytosis of shed photoreceptor outer segments (POS) by the retinal pigment epithelium (RPE) is required to sustain the visual function. Recent reports revealed that POS phagocytosis is progressed with LC3-associated manner. Patients with age-related macular degeneration (AMD) had impaired autophagic degradation in the RPE. Nrf2 is a key antioxidant transcriptional regulator that ameliorates oxidative stress which is another contributor to AMD pathogenesis. Nrf2 activation also induces the autophagy receptor protein, p62. However, the role of the Nrf2-p62 pathway in LC3-associated phagocytosis of POS is poorly understood. Here, we investigated the relationships between Nrf2 activation and POS phagocytosis progression. A triterpenoid Nrf2 activator, RS9, facilitated POS uptake into phagolysosomes in RPE cells. RS9 also induced the expression of the autophagy-related proteins, LC3-II and p62, as well as phase-2 antioxidant enzymes. The effect of RS9 on POS phagocytosis was abolished by autophagy inhibition. Unexpectedly, p62 knockdown did not inhibit the effect of RS9 on POS phagocytosis, although, RS9-mediated LC3-II induction by RS9 was inhibited in p62 knockdown RPE cells. We also found that RS9 activated the AMPKα-mTOR signaling pathway earlier than p62 induction. Knockdown of AMPKα1, but not α2, inhibited the RS9-mediated activation of LC3-associated phagocytosis and RS9-mediated induction of LC3-II. Furthermore, intravitreal treatment of RS9 to adult mice decreased the size of POS phagolysosomes after light exposure. Collectively, these results showed that RS9-mediated activation of POS phagocytosis was mainly ascribed to the enhancement of autophagy via AMPKα1 activation. Our findings reveal novel effects of Nrf2 and AMPK α1 activation that contribute to the maintenance of the RPE function via LC3-associated POS phagocytosis. (262 words/unlimited).
    Keywords:  AMP-Activated protein kinase (AMPK); Age-related macular degeneration (AMD); LC3-Associated phagocytosis; Nuclear factor erythroid 2-related factor 2 (Nrf2); Retinal pigment epithelium (RPE); p62
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.03.012
  3. Front Mol Neurosci. 2020 ;13 37
    Protein Aggregation and Dysfunction of Autophagy-Lysosomal Pathway: A Vicious Cycle in Lysosomal Storage Diseases.
    Antonio Monaco, Alessandro Fraldi.
      Many neurodegenerative conditions are characterized by the deposition of protein aggregates (mainly amyloid-like) in the central nervous system (CNS). In post-mitotic CNS cells protein aggregation causes cytotoxicity by interfering with various cellular functions. Mutations in different genes may directly cause protein aggregation. However, genetic factors together with aging may contribute to the onset of protein aggregation also by affecting cellular degradative functions, in particular the autophagy-lysosomal pathway (ALP). Increasing body of evidence show that ALP dysfunction and protein aggregation are functionally interconnected and induce each other during neurodegenerative processes. We will summarize the findings supporting these concepts by focusing on lysosomal storage diseases (LSDs), a class of metabolic inherited conditions characterized by global lysosomal dysfunction and often associated to a severe neurodegenerative course. We propose a model by which the inherited lysosomal defects initiate aggregate-prone protein deposition, which, in turns, worsen ALP degradation function, thus generating a vicious cycle, which boost neurodegenerative cascades.
    Keywords:  amyloid aggregation; autophagy; lysosomal storage disease; lysosome; molecular therapy of neurodegenerative diseases
    DOI:  https://doi.org/10.3389/fnmol.2020.00037
  4. Biochem Biophys Res Commun. 2020 Mar 20. pii: S0006-291X(20)30531-3. [Epub ahead of print]
    Ibudilast enhances the clearance of SOD1 and TDP-43 aggregates through TFEB-mediated autophagy and lysosomal biogenesis: The new molecular mechanism of ibudilast and its implication for neuroprotective therapy.
    Yanming Chen, Hongfeng Wang, Zheng Ying, Qingzhi Gao.
      A key feature of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders including Alzheimer disease (AD), Parkinson disease (PD) and Huntington's disease (HD) is abnormal aggregation and deposition of misfolded proteins. Previous studies have shown that autophagy plays an important role in the clearance of disease-linked protein aggregates. In the current study, we report that ibudilast, which is a non-selective inhibitor of phosphodiesterases (PDEs) and an anti-inflammation drug, can induce autophagy and lysosomal biogenesis through mammalian target of rapamycin complex 1 - transcription factor EB (mTORC1-TFEB) signaling. We have found that ibudilast significantly enhances the clearance of disease-linked TAR DNA binding protein (TDP-43) and superoxide dismutase 1 (SOD1) protein aggregates in transfected cellular models carrying corresponding gene mutations. The mechanistic study revealed that ibudilast could markedly enhance TFEB nuclear translocation and increase the autolysosomes by inhibiting mTORC1 activity. We have also demonstrated that ibudilast could protect TDP-43-induced cytotoxicity in motor neuron-like NSC-34 cells. Collectively, our study identifies ibudilast as an autophagy enhancer and provides insights into the molecular basis of ibudilast for the potential treatment of several neurodegenerative disorders.
    Keywords:  Autophagy; Ibudilast; Neurodegenerative disease; Protein aggregation; TDP-43
    DOI:  https://doi.org/10.1016/j.bbrc.2020.03.051
  5. Nat Cell Biol. 2020 Mar 16.
    Copper is an essential regulator of the autophagic kinases ULK1/2 to drive lung adenocarcinoma.
    Tiffany Tsang, Jessica M Posimo, Andrea A Gudiel, Michelle Cicchini, David M Feldser, Donita C Brady.
      Although the transition metal copper (Cu) is an essential nutrient that is conventionally viewed as a static cofactor within enzyme active sites, a non-traditional role for Cu as a modulator of kinase signalling is emerging. Here, we found that Cu is required for the activity of the autophagic kinases ULK1 and ULK2 (ULK1/2) through a direct Cu-ULK1/2 interaction. Genetic loss of the Cu transporter Ctr1 or mutations in ULK1 that disrupt the binding of Cu reduced ULK1/2-dependent signalling and the formation of autophagosome complexes. Increased levels of intracellular Cu are associated with starvation-induced autophagy and are sufficient to enhance ULK1 kinase activity and, in turn, autophagic flux. The growth and survival of lung tumours driven by KRASG12D is diminished in the absence of Ctr1, is dependent on ULK1 Cu binding and is associated with reduced levels of autophagy and signalling. These findings suggest a molecular basis for exploiting Cu-chelation therapy to prevent autophagy signalling to limit proliferation and improve patient survival in cancer.
    DOI:  https://doi.org/10.1038/s41556-020-0481-4
  6. Curr Opin Cell Biol. 2020 Mar 20. pii: S0955-0674(20)30035-1. [Epub ahead of print]65 50-57
    Autophagosomes are formed at a distinct cellular structure.
    David M Hollenstein, Claudine Kraft.
      Autophagy is characterized by the formation of double-membrane vesicles called autophagosomes, which deliver bulk cytoplasmic material to the lytic compartment of the cell for degradation. Autophagosome formation is initiated by assembly and recruitment of the core autophagy machinery to distinct cellular sites, referred to as phagophore assembly sites (PAS) in yeast or autophagosome formation sites in other organisms. A large number of autophagy proteins involved in the formation of autophagosomes has been identified; however, how the individual components of the PAS are assembled and how they function to generate autophagosomes remains a fundamental question. Here, we highlight recent studies that provide molecular insights into PAS organization and the role of the endoplasmic reticulum and the vacuole in autophagosome formation.
    Keywords:  ATG1; ATG12; ATG13; ATG16; ATG17; ATG18; ATG2; ATG29; ATG31; ATG5; Autophagosome; Autophagosome formation site; Autophagy; ER; Isolation membrane; Lipid transfer; Liquid droplet; Organelle contact site; PAS; Phagophore; Phagophore assembly site; Phase separation; Pre-autophagosomal structure; Tether; VAC8; Vacuole
    DOI:  https://doi.org/10.1016/j.ceb.2020.02.012
  7. FASEB J. 2020 Mar 22.
    AMPK activation induces mitophagy and promotes mitochondrial fission while activating TBK1 in a PINK1-Parkin independent manner.
    Alex P Seabright, Nicholas H F Fine, Jonathan P Barlow, Samuel O Lord, Ibrahim Musa, Alexander Gray, Jack A Bryant, Manuel Banzhaf, Gareth G Lavery, D Grahame Hardie, David J Hodson, Andrew Philp, Yu-Chiang Lai.
      Mitophagy is a key process regulating mitochondrial quality control. Several mechanisms have been proposed to regulate mitophagy, but these have mostly been studied using stably expressed non-native proteins in immortalized cell lines. In skeletal muscle, mitophagy and its molecular mechanisms require more thorough investigation. To measure mitophagy directly, we generated a stable skeletal muscle C2C12 cell line, expressing a mitophagy reporter construct (mCherry-green fluorescence protein-mtFIS1101-152 ). Here, we report that both carbonyl cyanide m-chlorophenyl hydrazone (CCCP) treatment and adenosine monophosphate activated protein kinase (AMPK) activation by 991 promote mitochondrial fission via phosphorylation of MFF and induce mitophagy by ~20%. Upon CCCP treatment, but not 991, ubiquitin phosphorylation, a read-out of PTEN-induced kinase 1 (PINK1) activity, and Parkin E3 ligase activity toward CDGSH iron sulfur domain 1 (CISD1) were increased. Although the PINK1-Parkin signaling pathway is active in response to CCCP treatment, we observed no change in markers of mitochondrial protein content. Interestingly, our data shows that TANK-binding kinase 1 (TBK1) phosphorylation is increased after both CCCP and 991 treatments, suggesting TBK1 activation to be independent of both PINK1 and Parkin. Finally, we confirmed in non-muscle cell lines that TBK1 phosphorylation occurs in the absence of PINK1 and is regulated by AMPK-dependent signaling. Thus, AMPK activation promotes mitophagy by enhancing mitochondrial fission (via MFF phosphorylation) and autophagosomal engulfment (via TBK1 activation) in a PINK1-Parkin independent manner.
    Keywords:  endogenous; mitophagy; skeletal muscle; tandem ubiquitin-binding entity (TUBE); ubiquitin
    DOI:  https://doi.org/10.1096/fj.201903051R
  8. Nat Commun. 2020 Mar 24. 11(1): 1535
    Autophagy lipidation machinery regulates axonal microtubule dynamics but is dispensable for survival of mammalian neurons.
    A Negrete-Hurtado, M Overhoff, S Bera, E De Bruyckere, K Schätzmüller, M J Kye, C Qin, M Lammers, V Kondylis, I Neundorf, N L Kononenko.
      Neurons maintain axonal homeostasis via employing a unique organization of the microtubule (MT) cytoskeleton, which supports axonal morphology and provides tracks for intracellular transport. Abnormal MT-based trafficking hallmarks the pathology of neurodegenerative diseases, but the exact mechanism regulating MT dynamics in axons remains enigmatic. Here we report on a regulation of MT dynamics by AuTophaGy(ATG)-related proteins, which previously have been linked to the autophagy pathway. We find that ATG proteins required for LC3 lipid conjugation are dispensable for survival of excitatory neurons and instead regulate MT stability via controlling the abundance of the MT-binding protein CLASP2. This function of ATGs is independent of their role in autophagy and requires the active zone protein ELKS1. Our results highlight a non-canonical role of ATG proteins in neurons and suggest that pharmacological activation of autophagy may not only promote the degradation of cytoplasmic material, but also impair axonal integrity via altering MT stability.
    DOI:  https://doi.org/10.1038/s41467-020-15287-9
  9. Curr Opin Cell Biol. 2020 Mar 23. pii: S0955-0674(20)30031-4. [Epub ahead of print]65 66-71
    Inter-organelle lipid transfer: a channel model for Vps13 and chorein-N motif proteins.
    Joshua A Lees, Karin M Reinisch.
      Membrane contact sites, where two organelles are in close proximity, are critical regulators of cellular membrane homeostasis, with roles in signaling, lipid metabolism, and ion dynamics. A growing catalog of specialized lipid transfer proteins carry out lipid exchange at these sites. Currently characterized eukaryotic lipid transport proteins are shuttles that typically extract a single lipid from the membrane of the donor organelle, solubilize it during transport through the cytosol, and deposit it in the acceptor organelle membrane. Here, we highlight the recently identified chorein_N family of lipid transporters, including the Vps13 proteins and the autophagy protein Atg2. These are elongated proteins that, distinct from previously characterized transport proteins, bind tens of lipids at once. They feature an extended channel, most likely lined with hydrophobic residues. We discuss the possibility that they are not shuttles but instead are bridges between membranes, with lipids traversing the cytosol via the hydrophobic channel.
    Keywords:  Chorein_N motif; Lipid transfer proteins; Membrane contact sites
    DOI:  https://doi.org/10.1016/j.ceb.2020.02.008
  10. Biochem Biophys Res Commun. 2020 Mar 19. pii: S0006-291X(20)30543-X. [Epub ahead of print]
    Lysine-specific demethylase 3A is important for autophagic occurrence.
    Joomyung Kim, Seon Ah Choi, Jaebeom Kim, Hyunkyung Kim, Sung Hee Baek.
      Autophagy is an essential process to maintain cell survival and homeostasis under various stress conditions. Here, we report that lysine-specific demethylase 3A (KDM3A) plays an important role in starvation-induced autophagy. Using Kdm3a knockout mice, we demonstrate that KDM3A is crucial for proper hepatic autophagy in vivo. Hepatic mRNA expression analysis and ChIP assay in WT and Kdm3a knockout mouse livers reveal that KDM3A activates autophagy genes by reducing histone H3K9me2 levels upon fasting. Together, our finding represents previously unidentified function of KDM3A as a key regulator of autophagy, implicating potential therapeutic approaches for autophagy-related diseases.
    Keywords:  Autophagy; H3K9 demethylation; KDM3A
    DOI:  https://doi.org/10.1016/j.bbrc.2020.03.058
  11. Antioxid Redox Signal. 2020 Mar 25.
    Cell Senescence, DNA Damage and Metabolism.
    Riva Shmulevich, Valery Krizhanovsky.
      SIGNIFICANCE: Senescence is an essential biological process that blocks tumorigenesis, limits tissue damage and aids embryonic development. However, once senescent cells accumulate in tissues during aging, they promote development of age-related disease and limit healthspan. It is therefore crucial to gain a better understanding of the mechanisms controlling cellular senescence. Recent Advances: Cellular metabolism plays a significant role in regulation of various signaling process involved in cell senescence. In recent years, our understanding of the intimate relationship between cell metabolism, cell signaling, and cellular senescence has greatly improved.CRITICAL ISSUES: In this review, we discuss metabolic pathways in senescent cells and the impact of these pathways on DNA damage response and senescence associated secretory phenotype (SASP).
    FUTURE DIRECTIONS: Future research should elucidate metabolic mechanisms that promote specific alterations in senescent cell phenotype, with the final aim of developing new therapeutic strategies.
    DOI:  https://doi.org/10.1089/ars.2020.8043
  12. Aging (Albany NY). 2020 Mar 22. 12
    ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging.
    Jing Zhao, Lei Zhang, Aiping Lu, Yingchao Han, Debora Colangelo, Christina Bukata, Alex Scibetta, Matthew J Yousefzadeh, Xuesen Li, Aditi U Gurkar, Sara J McGowan, Luise Angelini, Ryan O'Kelly, Hongshuai Li, Lana Corbo, Tokio Sano, Heather Nick, Enrico Pola, Smitha P S Pilla, Warren C Ladiges, Nam Vo, Johnny Huard, Laura J Niedernhofer, Paul D Robbins.
      NF-κB is a transcription factor activated in response to inflammatory, genotoxic and oxidative stress and important for driving senescence and aging. Ataxia-telangiectasia mutated (ATM) kinase, a core component of DNA damage response signaling, activates NF-κB in response to genotoxic and oxidative stress via post-translational modifications. Here we demonstrate that ATM is activated in senescent cells in culture and murine tissues from Ercc1-deficient mouse models of accelerated aging, as well as naturally aged mice. Genetic and pharmacologic inhibition of ATM reduced activation of NF-κB and markers of senescence and the senescence-associated secretory phenotype (SASP) in senescent Ercc1-/- MEFs. Ercc1-/Δ mice heterozygous for Atm have reduced NF-κB activity and cellular senescence, improved function of muscle-derived stem/progenetor cells (MDSPCs) and extended healthspan with reduced age-related pathology especially age-related bone and intervertebral disc pathologies. In addition, treatment of Ercc1-/∆ mice with the ATM inhibitor KU-55933 suppressed markers of senescence and SASP. Taken together, these results demonstrate that the ATM kinase is a major mediator of DNA damage-induced, NF-κB-mediated cellular senescence, stem cell dysfunction and aging and thus represents a therapeutic target to slow the progression of aging.
    Keywords:  ATM; DNA damage response; NF-κB; aging; cellular senescence
    DOI:  https://doi.org/10.18632/aging.102863
  13. Pharmacology. 2020 Mar 20. 1-9
    Dihydrotanshinone I Increase Amyloid-β Clearance and Decrease Tau Phosphorylation via Enhancing Autophagy.
    Zhonglei Bao, Huixue Zhang, Hong Jiao, Xiaojie Chu, Jin Fu, Lihua Wang.
      INTRODUCTION: The plaques formed by amyloid-β (Aβ) accumulation and neurofibrillary tangles formed by hyper-phosphorylated tau protein are the 2 major pathologies of Alzheimer's disease (AD). Recently, autophagy is considered to be a self-degradation process of preserved cytoplasmic abnormal substances, including Aβ and tau.METHODS: α-Screen assay is used to discover a new mammalian target of rapamycin (mTOR) signaling inhibitor, and laser scanning confocal microscopic analysis is used to investigate the autophagy formation. Lastly, ELISA and Western blot assays are used to identify the mTOR signaling inhibitor effect on Aβ and tau and the underlying mechanism.
    RESULTS: In the current study, we discover that dihydrotanshinone I (DTS I), extracted from Radix Salviae, can obviously inhibit mTOR phosphorylation and increase autophagy via increasing AMPK phosphorylation. Further study demonstrates that DTS I increases Aβ clearance and decreases Tau phosphorylation through autophagy enhancement involved with AMPK/mTOR pathway.
    CONCLUSION: Our study indicates that DTS I can increase Aβ clearance and decrease Tau phosphorylation via autophagy enhancing involved with AMPK/mTOR pathway, which highlights the therapeutic potential of DTS I for the treatment of AD.
    Keywords:  Alzheimer’s disease; Amyloid-β; Autophagy; Dihydrotanshinone I; Tau
    DOI:  https://doi.org/10.1159/000503792
  14. Int J Mol Sci. 2020 Mar 24. pii: E2240. [Epub ahead of print]21(6):
    SIRT2 Affects Primary Cilia Formation by Regulating mTOR Signaling in Retinal Pigmented Epithelial Cells.
    Jeaho Lim, Juyoung Son, Jaewook Ryu, Ja-Eun Kim.
      SIRT2, a member of the Class III HDAC family, participates in diverse cellular processes and regulates several pathological conditions. Although a few reports show that SIRT2 regulates the cell cycle, the causes and outcomes of SIRT2-dependent cell proliferation remain unclear. Here, we examined the effects of SIRT2 suppression in human RPE1 cells using siRNA targeting SIRT2, and AK-1, a SIRT2-specific inhibitor. The number of primary cilia in SIRT2-suppressed cells increased under serum-present conditions. Suppressing SIRT2 induced cell cycle arrest at G0/G1 phase by inactivating mammalian target of rapamycin (mTOR) signaling, possibly through mTORC1. Treatment with torin 1, an inhibitor of mTORC1/mTORC2, yielded results similar to those observed after SIRT2 suppression. However, SIRT2 suppression did not affect primary cilia formation or mTOR signaling following serum starvation. This suggests that SIRT2 acts as a critical sensor that links growth factor-dependent signal transduction and primary cilia formation by regulating the cell cycle.
    Keywords:  SIRT2; cell cycle; cilia; mTOR
    DOI:  https://doi.org/10.3390/ijms21062240
  15. Aging (Albany NY). 2020 Mar 24. 12
    Verapamil extends lifespan in Caenorhabditis elegans by inhibiting calcineurin activity and promoting autophagy.
    Wenwen Liu, Huiling Lin, Zhifan Mao, Lanxin Zhang, Keting Bao, Bei Jiang, Conglong Xia, Wenjun Li, Zelan Hu, Jian Li.
      Previous evidence has revealed that increase in intracellular levels of calcium promotes cellular senescence. However, whether calcium channel blockers (CCBs) can slow aging and extend lifespan is still unknown. In this study, we showed that verapamil, an L-type calcium channel blocker, extended the Caenorhabditis elegans (C. elegans) lifespan and delayed senescence in human lung fibroblasts. Verapamil treatment also improved healthspan in C. elegans as reflected by several age-related physiological parameters, including locomotion, thrashing, age-associated vulval integrity, and osmotic stress resistance. We also found that verapamil acted on the α1 subunit of an L-type calcium channel in C. elegans. Moreover, verapamil extended worm lifespan by inhibiting calcineurin activity. Furthermore, verapamil significantly promoted autophagy as reflected by the expression levels of LGG-1/LC3 and the mRNA levels of autophagy-related genes. In addition, verapamil could not further induce autophagy when tax-6, calcineurin gene, was knocked down, indicating that verapamil-induced lifespan extension is mediated via promoting autophagy processes downstream of calcineurin. In summary, our study provided mechanistic insights into the anti-aging effect of verapamil in C. elegans.
    Keywords:  Caenorhabditis elegans; anti-aging; autophagy; cell senescence; verapamil
    DOI:  https://doi.org/10.18632/aging.102951
  16. Aging (Albany NY). 2020 Mar 26. 12
    Role of mitochondrial quality control in the pathogenesis of nonalcoholic fatty liver disease.
    Ruibing Li, Sam Toan, Hao Zhou.
      Nutrient oversupply and mitochondrial dysfunction play central roles in nonalcoholic fatty liver disease (NAFLD). The mitochondria are the major sites of β-oxidation, a catabolic process by which fatty acids are broken down. The mitochondrial quality control (MQC) system includes mitochondrial fission, fusion, mitophagy and mitochondrial redox regulation, and is essential for the maintenance of the functionality and structural integrity of the mitochondria. Excessive and uncontrolled production of reactive oxygen species (ROS) in the mitochondria damages mitochondrial components, including membranes, proteins and mitochondrial DNA (mtDNA), and triggers the mitochondrial pathway of apoptosis. The functionality of some damaged mitochondria can be restored by fusion with normally functioning mitochondria, but when severely damaged, mitochondria are segregated from the remaining functional mitochondrial network through fission and are eventually degraded via mitochondrial autophagy, also called as mitophagy. In this review, we describe the functions and mechanisms of mitochondrial fission, fusion, oxidative stress and mitophagy in the development and progression of NAFLD.
    Keywords:  NAFLD; fission; fusion; mitochondrial quality control; mitophagy
    DOI:  https://doi.org/10.18632/aging.102972
  17. J Clin Med. 2020 Mar 24. pii: E892. [Epub ahead of print]9(3):
    Mitophagy in Cardiovascular Diseases.
    Giampaolo Morciano, Simone Patergnani, Massimo Bonora, Gaia Pedriali, Anna Tarocco, Esmaa Bouhamida, Saverio Marchi, Gina Ancora, Gabriele Anania, Mariusz R Wieckowski, Carlotta Giorgi, Paolo Pinton.
      Cardiovascular diseases are one of the leading causes of death. Increasing evidence has shown that pharmacological or genetic targeting of mitochondria can ameliorate each stage of these pathologies, which are strongly associated with mitochondrial dysfunction. Removal of inefficient and dysfunctional mitochondria through the process of mitophagy has been reported to be essential for meeting the energetic requirements and maintaining the biochemical homeostasis of cells. This process is useful for counteracting the negative phenotypic changes that occur during cardiovascular diseases, and understanding the molecular players involved might be crucial for the development of potential therapies. Here, we summarize the current knowledge on mitophagy (and autophagy) mechanisms in the context of heart disease with an important focus on atherosclerosis, ischemic heart disease, cardiomyopathies, heart failure, hypertension, arrhythmia, congenital heart disease and peripheral vascular disease. We aim to provide a complete background on the mechanisms of action of this mitochondrial quality control process in cardiology and in cardiac surgery by also reviewing studies on the use of known compounds able to modulate mitophagy for cardioprotective purposes.
    Keywords:  autophagy; cardiovascular diseases; mitochondria; mitophagy
    DOI:  https://doi.org/10.3390/jcm9030892
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