-
Cell Metabolism Nov 2022Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation (OXPHOS) system of...
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.
Topics: Mice; Animals; Mitochondrial Proteins; Ferroptosis; Mitochondria; Electron Transport Complex IV; Cardiomyopathies; Membrane Proteins; Alkyl and Aryl Transferases; Metalloproteases
PubMed: 36113464
DOI: 10.1016/j.cmet.2022.08.017 -
Endocrine Reviews Nov 2023Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the... (Review)
Review
Pregnancy-associated plasma protein-A (PAPP-A) was first identified in the early 1970s as a placental protein of unknown function, present at high concentrations in the circulation of pregnant women. In the mid-to-late 1990s, PAPP-A was discovered to be a metzincin metalloproteinase, expressed by many nonplacental cells, that regulates local insulin-like growth factor (IGF) activity through cleavage of high-affinity IGF binding proteins (IGFBPs), in particular IGFBP-4. With PAPP-A as a cell surface-associated enzyme, the reduced affinity of the cleavage fragments results in increased IGF available to bind and activate IGF receptors in the pericellular environment. This proteolytic regulation of IGF activity is important, since the IGFs promote proliferation, differentiation, migration, and survival in various normal and cancer cells. Thus, there has been a steady growth in investigation of PAPP-A structure and function outside of pregnancy. This review provides historical perspective on the discovery of PAPP-A and its structure and cellular function, highlights key studies of the first 50 years in PAPP-A research, and introduces new findings from recent years.
Topics: Pregnancy; Humans; Female; Pregnancy-Associated Plasma Protein-A; Placenta; Metalloproteases; Cell Differentiation; Insulin-Like Growth Factor I
PubMed: 37267421
DOI: 10.1210/endrev/bnad017 -
Archives of Toxicology Jun 2022Tetanus and botulinum neurotoxins cause the neuroparalytic syndromes of tetanus and botulism, respectively, by delivering inside different types of neurons,... (Review)
Review
Tetanus and botulinum neurotoxins cause the neuroparalytic syndromes of tetanus and botulism, respectively, by delivering inside different types of neurons, metalloproteases specifically cleaving the SNARE proteins that are essential for the release of neurotransmitters. Research on their mechanism of action is intensively carried out in order to devise improved therapies based on antibodies and chemical drugs. Recently, major results have been obtained with human monoclonal antibodies and with single chain antibodies that have allowed one to neutralize the metalloprotease activity of botulinum neurotoxin type A1 inside neurons. In addition, a method has been devised to induce a rapid molecular evolution of the metalloprotease domain of botulinum neurotoxin followed by selection driven to re-target the metalloprotease activity versus novel targets with respect to the SNARE proteins. At the same time, an intense and wide spectrum clinical research on novel therapeutics based on botulinum neurotoxins is carried out, which are also reviewed here.
Topics: Botulinum Toxins, Type A; Clostridium botulinum; Humans; Neurotoxins; SNARE Proteins; Tetanus
PubMed: 35333944
DOI: 10.1007/s00204-022-03271-9 -
Life Sciences Oct 2019Extensive degeneration of articular cartilage (AC) is a primary event in the pathogenesis of osteoarthritis (OA) and other types of joint and bone inflammation. OA... (Review)
Review
Extensive degeneration of articular cartilage (AC) is a primary event in the pathogenesis of osteoarthritis (OA) and other types of joint and bone inflammation. OA results in the loss of joint function, usually accompanied by severe pain, and are the most common type of arthritis, affecting more than 10% of adults. The characteristic signs of OA are progressive cartilage destruction and, eventually, complete loss of chondrocytes. A key enzyme responsible for these degenerative changes in cartilage is matrix metalloproteinase-13 (MMP-13), which is thought to be a major contributor to the degenerative process occurring during OA pathogenesis. The aim of the present review is to shed light on the general role of MMPs, with special emphasis on MMP-13, in the induction of OA and the general basis of OA treatment. The pathogenic mechanism of this highly prevalent disease is not clear, and no effective disease-modifying treatment is currently available. Any updated information about OA treatment in human patients will also benefit companion animals such as horses and dogs, which also suffer from OA. Selective inhibition of MMP-13 seems to be an attractive therapeutic strategy.
Topics: Animals; Cartilage, Articular; Drug Discovery; Extracellular Matrix; Humans; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Osteoarthritis
PubMed: 31445934
DOI: 10.1016/j.lfs.2019.116786 -
Cell Death & Disease Mar 2023Pancreatic cancer remains one of the most lethal diseases with a relatively low 5-year survival rate, and gemcitabine-based chemoresistance occurs constantly....
Pancreatic cancer remains one of the most lethal diseases with a relatively low 5-year survival rate, and gemcitabine-based chemoresistance occurs constantly. Mitochondria, as the power factory in cancer cells, are involved in the process of chemoresistance. The dynamic balance of mitochondria is under the control of mitophagy. Stomatin-like protein 2 (STOML2) is located in the mitochondrial inner membrane and is highly expressed in cancer cells. In this study, using a tissue microarray (TMA), we found that high STOML2 expression was correlated with higher survival of patients with pancreatic cancer. Meanwhile, the proliferation and chemoresistance of pancreatic cancer cells could be retarded by STOML2. In addition, we found that STOML2 was positively related to mitochondrial mass and negatively related to mitophagy in pancreatic cancer cells. STOML2 stabilized PARL and further prevented gemcitabine-induced PINK1-dependent mitophagy. We also generated subcutaneous xenografts to verify the enhancement of gemcitabine therapy induced by STOML2. These findings suggested that STOML2 regulated the mitophagy process through the PARL/PINK1 pathway, thereby reducing the chemoresistance of pancreatic cancer. STOML2-overexpression targeted therapy might be helpful for gemcitabine sensitization in the future.
Topics: Humans; Blood Proteins; Gemcitabine; Metalloproteases; Mitochondria; Mitochondrial Proteins; Mitophagy; Pancreatic Neoplasms; Protein Kinases; Ubiquitin-Protein Ligases; Membrane Proteins
PubMed: 36906621
DOI: 10.1038/s41419-023-05711-5 -
Cell Aug 2023The endopeptidase ADAM10 is a critical catalyst for the regulated proteolysis of key drivers of mammalian development, physiology, and non-amyloidogenic cleavage of APP...
The endopeptidase ADAM10 is a critical catalyst for the regulated proteolysis of key drivers of mammalian development, physiology, and non-amyloidogenic cleavage of APP as the primary α-secretase. ADAM10 function requires the formation of a complex with a C8-tetraspanin protein, but how tetraspanin binding enables positioning of the enzyme active site for membrane-proximal cleavage remains unknown. We present here a cryo-EM structure of a vFab-ADAM10-Tspan15 complex, which shows that Tspan15 binding relieves ADAM10 autoinhibition and acts as a molecular measuring stick to position the enzyme active site about 20 Å from the plasma membrane for membrane-proximal substrate cleavage. Cell-based assays of N-cadherin shedding establish that the positioning of the active site by the interface between the ADAM10 catalytic domain and the bound tetraspanin influences selection of the preferred cleavage site. Together, these studies reveal the molecular mechanism underlying ADAM10 proteolysis at membrane-proximal sites and offer a roadmap for its modulation in disease.
Topics: Animals; ADAM10 Protein; Amyloid Precursor Protein Secretases; Mammals; Proteolysis; Tetraspanins; Humans
PubMed: 37516108
DOI: 10.1016/j.cell.2023.06.026 -
General and Comparative Endocrinology Dec 2021Changes in expression or activation of various metalloproteases including matrix metalloproteases (Mmp), a disintegrin and metalloprotease (Adam) and a disintegrin and... (Review)
Review
Changes in expression or activation of various metalloproteases including matrix metalloproteases (Mmp), a disintegrin and metalloprotease (Adam) and a disintegrin and metalloprotease with thrombospondin motif (Adamts), and their endogenous inhibitors (tissue inhibitors of metalloproteases, Timp), have been shown to be critical for ovulation in various species from studies in past decades. Some of these metalloproteases such as Adamts1, Adamts9, Mmp2, and Mmp9 have also been shown to be regulated by luteinizing hormone (LH) and/or progestin, which are essential triggers for ovulation in all vertebrate species. Most of these metalloproteases also express broadly in various tissues and cells including germ cells and somatic gonad cells. Thus, metalloproteases likely play roles in gonad formation processes comprising primordial germ cell (PGC) migration, development of germ and somatic cells, and sex determination. However, our knowledge on the functions and mechanisms of metalloproteases in these processes in vertebrates is still lacking. This review will summarize our current knowledge on the metalloproteases in ovulation and gonad formation with emphasis on PGC migration and germ cell development.
Topics: Animals; Female; Germ Cells; Gonads; Luteinizing Hormone; Matrix Metalloproteinases; Ovulation
PubMed: 34606745
DOI: 10.1016/j.ygcen.2021.113924 -
Biological Chemistry Aug 2021A disintegrin and metalloprotease (ADAM) 17 is a membrane bound protease, involved in the cleavage and thus regulation of various membrane proteins, which are critical... (Review)
Review
A disintegrin and metalloprotease (ADAM) 17 is a membrane bound protease, involved in the cleavage and thus regulation of various membrane proteins, which are critical during liver injury. Among ADAM17 substrates are tumor necrosis factor α (TNFα), tumor necrosis factor receptor 1 and 2 (TNFR1, TNFR2), the epidermal growth factor receptor (EGFR) ligands amphiregulin (AR) and heparin-binding-EGF-like growth factor (HB-EGF), the interleukin-6 receptor (IL-6R) and the receptor for a hepatocyte growth factor (HGF), c-Met. TNFα and its binding receptors can promote liver injury by inducing apoptosis and necroptosis in liver cells. Consistently, hepatocyte specific deletion of ADAM17 resulted in increased liver cell damage following CD95 stimulation. IL-6 trans-signaling is critical for liver regeneration and can alleviate liver damage. EGFR ligands can prevent liver damage and deletion of amphiregulin and HB-EGF can result in increased hepatocyte death and reduced proliferation. All of which indicates that ADAM17 has a central role in liver injury and recovery from it. Furthermore, inactive rhomboid proteins (iRhom) are involved in the trafficking and maturation of ADAM17 and have been linked to liver damage. Taken together, ADAM17 can contribute in a complex way to liver damage and injury.
Topics: ADAM17 Protein; Animals; Humans; Liver
PubMed: 34192832
DOI: 10.1515/hsz-2021-0149 -
American Journal of Physiology. Cell... Sep 2020Vascular remodeling is the adaptive response to various physiological and pathophysiological alterations that are closely related to aging and vascular diseases.... (Review)
Review
Vascular remodeling is the adaptive response to various physiological and pathophysiological alterations that are closely related to aging and vascular diseases. Understanding the mechanistic regulation of vascular remodeling may be favorable for discovering potential therapeutic targets and strategies. The extracellular matrix (ECM), including matrix proteins and their degradative metalloproteases, serves as the main component of the microenvironment and exhibits dynamic changes during vascular remodeling. This process involves mainly the altered composition of matrix proteins, metalloprotease-mediated degradation, posttranslational modification of ECM proteins, and altered topographical features of the ECM. To date, adequate studies have demonstrated that ECM dynamics also play a critical role in vascular remodeling in various diseases. Here, we review these related studies, summarize how ECM dynamics control vascular remodeling, and further indicate potential diagnostic biomarkers and therapeutic targets in the ECM for corresponding vascular diseases.
Topics: Animals; Biomarkers; Extracellular Matrix; Extracellular Matrix Proteins; Humans; Matrix Metalloproteinases; Vascular Diseases; Vascular Remodeling
PubMed: 32579472
DOI: 10.1152/ajpcell.00147.2020 -
Cellular and Molecular Life Sciences :... Aug 2019'A disintegrin and metalloproteases' (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active... (Review)
Review
'A disintegrin and metalloproteases' (ADAMs) are a family of transmembrane proteins with diverse functions in multicellular organisms. About half of the ADAMs are active metalloproteases and cleave numerous cell surface proteins, including growth factors, receptors, cytokines and cell adhesion proteins. The other ADAMs have no catalytic activity and function as adhesion proteins or receptors. Some ADAMs are ubiquitously expressed, others are expressed tissue specifically. This review highlights functions of ADAMs in the mammalian nervous system, including their links to diseases. The non-proteolytic ADAM11, ADAM22 and ADAM23 have key functions in neural development, myelination and synaptic transmission and are linked to epilepsy. Among the proteolytic ADAMs, ADAM10 is the best characterized one due to its substrates Notch and amyloid precursor protein, where cleavage is required for nervous system development or linked to Alzheimer's disease (AD), respectively. Recent work demonstrates that ADAM10 has additional substrates and functions in the nervous system and its substrate selectivity may be regulated by tetraspanins. New roles for other proteolytic ADAMs in the nervous system are also emerging. For example, ADAM8 and ADAM17 are involved in neuroinflammation. ADAM17 additionally regulates neurite outgrowth and myelination and its activity is controlled by iRhoms. ADAM19 and ADAM21 function in regenerative processes upon neuronal injury. Several ADAMs, including ADAM9, ADAM10, ADAM15 and ADAM30, are potential drug targets for AD. Taken together, this review summarizes recent progress concerning substrates and functions of ADAMs in the nervous system and their use as drug targets for neurological and psychiatric diseases.
Topics: ADAM Proteins; Animals; Biological Transport; Epilepsy; Humans; Inflammation; Myelin Sheath; Nervous System; Potassium Channels; Proteolysis
PubMed: 31236626
DOI: 10.1007/s00018-019-03173-7