The lysosomal-mitochondrial axis theory of postmitotic aging and cell death.


:Aging (senescence) is characterized by a progressive accumulation of macromolecular damage, supposedly due to a continuous minor oxidative stress associated with mitochondrial respiration. Aging mainly affects long-lived postmitotic cells, such as neurons and cardiac myocytes, which neither divide and dilute damaged structures, nor are replaced by newly differentiated cells. Because of inherent imperfect lysosomal degradation (autophagy) and other self-repair mechanisms, damaged structures (biological "garbage") progressively accumulate within such cells, both extra- and intralysosomally. Defective mitochondria and aggregated proteins are the most typical forms of extralysosomal "garbage", while lipofuscin that forms due to iron-catalyzed oxidation of autophagocytosed or heterophagocytosed material, represents intralysosomal "garbage". Based on findings that autophagy is diminished in lipofuscin-loaded cells and that cellular lipofuscin content positively correlates with oxidative stress and mitochondrial damage, we have proposed the mitochondrial-lysosomal axis theory of aging, according to which mitochondrial turnover progressively declines with age, resulting in decreased ATP production and increased oxidative damage. Due to autophagy of ferruginous material, lysosomes contain a pool of redox-active iron, which makes these organelles particularly susceptible to oxidative damage. Oxidant-mediated destabilization of lysosomal membranes releases hydrolytic enzymes to the cytosol, eventuating in cell death (either apoptotic or necrotic depending on the magnitude of the insult), while chelation of the intralysosomal pool of redox-active iron prevents these effects. In relation to the onset of oxidant-induced apoptosis, but after the initiating lysosomal rupture, cytochrome c is released from mitochondria and caspases are activated. Mitochondrial damage follows the release of lysosomal hydrolases, which may act either directly or indirectly, through activation of phospholipases or pro-apoptotic proteins such as Bid. Additional lysosomal rupture seems to be a consequence of a transient oxidative stress of mitochondrial origin that follows the attack by lysosomal hydrolases and/or phospholipases, creating an amplifying loop system.


Chem Biol Interact


Terman A,Gustafsson B,Brunk UT




Has Abstract


2006-10-27 00:00:00














  • The Gillings Sampler--an electrostatic air sampler as an alternative method for aerosol in vitro exposure studies.

    abstract::There is growing interest in studying the toxicity and health risk of exposure to multi-pollutant mixtures found in ambient air, and the U.S. Environmental Protection Agency (EPA) is moving towards setting standards for these types of mixtures. Additionally, the Health Effects Institute's strategic plan aims to develo...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Zavala J,Lichtveld K,Ebersviller S,Carson JL,Walters GW,Jaspers I,Jeffries HE,Sexton KG,Vizuete W

    更新日期:2014-09-05 00:00:00

  • Purification and characterization of two distinct aldehyde-oxidizing enzymes from the liver of black seabream.

    abstract::Two aldehyde dehydrogenases (ALDH) were purified from the liver of black seabream (Acanthopagrus schlegeli). Chromatography of the liver homogenate on an alpha-cyanocinnamate-Sepharose affinity column results in two activity peaks using acetaldehyde as the substrate. The eluate was subjected to another affinity chroma...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Fong WP,Cheng CH,Tang WK

    更新日期:2003-02-01 00:00:00

  • Selenium in the maintenance and therapy of HIV-infected patients.

    abstract::Due to its antiviral effects and its importance for all immunological functions, the administration of selenium is suggested as a supportive measure in early as well as in advanced stages of HIV-induced disease. Initial observations on the effects of selenium supplementation in HIV-infected patients indicate that sele...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章,评审


    authors: Schrauzer GN,Sacher J

    更新日期:1994-06-01 00:00:00

  • Catalytic parameters for the hydrolysis of butyrylthiocholine by human serum butyrylcholinesterase variants.

    abstract::Catalysed hydrolysis of butyrylthiocholine (BTCh) by the usual (UU), fluoride-resistant (FS), AK, AJ and atypical (AA) human serum butyrylcholinesterase (EC variants was measured in phosphate buffer pH 7.4 at 25 degrees C. pS-curves for all phenotypes were S-shaped; the activities rose to a plateau with incre...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Simeon-Rudolf V,Reiner E,Evans RT,George PM,Potter HC

    更新日期:1999-05-14 00:00:00

  • Lycium barbarum polysaccharides reduce intestinal ischemia/reperfusion injuries in rats.

    abstract::Inflammation and oxidative stress exert important roles in intestinal ischemia-reperfusion injury (IRI). Lycium barbarum polysaccharides (LBPs) have shown effective antioxidative and immunomodulatory functions in different models. The purpose of the present study was to assess the effects and potential mechanisms of L...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Yang X,Bai H,Cai W,Li J,Zhou Q,Wang Y,Han J,Zhu X,Dong M,Hu D

    更新日期:2013-08-25 00:00:00

  • Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions.

    abstract::Glucuronide conjugates represent one of the major types of naturally occurring phase 2 metabolites of xenobiotics and endobiotics. The process underlying their formation, glucuronidation, is normally considered detoxifying, because glucuronides usually possess less intrinsic biological or chemical activity than their ...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章,评审


    authors: Ritter JK

    更新日期:2000-12-01 00:00:00

  • Studies on rat hepatic hydroxysteroid sulfotransferase--immunochemistry, development and pI variants.

    abstract::Rat hepatic hydroxysteroid sulfotransferase with sulfoconjugates androsterone (androsterone-sulfating sulfotransferase) is an oligomer consisting of several subunits with distinct pI values but with the same molecular mass (pI variants). N-terminal amino acid sequences of the pI variants are all identical. The enzyme ...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Homma H,Nakagome I,Kamakura M,Hirota M,Takahashi M,Matsui M

    更新日期:1994-06-01 00:00:00

  • Effects of mercuric chloride on synchronized Chinese hamster ovary cells: survival and DNA replication.

    abstract::Chinese hamster ovary (CHO) cells in vitro were treated with HgCl2 at various stages in the cell cycle and the effects of this chemical on cell survival, DNA replication, and cell division were observed. In terms of survival the early G1 cells were the most sensitive to treatment, followed by late G1 and early S, whil...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Kasschau MR,Elder J,Meyn RE

    更新日期:1977-08-01 00:00:00

  • EMF protects cardiomyocytes against hypoxia-induced injury via heat shock protein 70 activation.

    abstract::Intracellular calcium (Ca(2+)i) overload induced by chronic hypoxia alters Ca(2+)i homeostasis, whereas ameliorating calcium homeostasis is believed to be responsible for cardioprotection. We hypothesize that cardioprotection by electromagnetic fields (EMF) exposure may restore Ca(2+)i homeostasis altered by hypoxia i...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Wei J,Tong J,Yu L,Zhang J

    更新日期:2016-03-25 00:00:00

  • Sodium acetate protects against nicotine-induced excess hepatic lipid in male rats by suppressing xanthine oxidase activity.

    abstract::Fatty liver is the hepatic consequence of chronic insulin resistance (IR) and related syndromes. It is mostly accompanied by inflammatory and oxidative molecules. Increased activity of xanthine oxidase (XO) exerts both inflammatory and oxidative effects and has been implicated in metabolic derangements including non-a...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Dangana EO,Omolekulo TE,Areola ED,Olaniyi KS,Soladoye AO,Olatunji LA

    更新日期:2020-01-25 00:00:00

  • Studies on the relationship between dimethylnitrosamine-demethylase activity and dimethylnitrosamine-dependent mutagenesis in Drosophila melanogaster.

    abstract::The relationship between dimethylnitrosamine (DMN) demethylase activity and DMN-induced mutagenesis was investigated in Drosophila melanogaster. The activity of DMN-demethylase was at least 10-fold greater in the Hikone-R strain than in three other Drosophila strains. However, the sex-linked recessive lethal (SLRL) mu...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Waters LC,Nix CE,Epler JL

    更新日期:1983-08-15 00:00:00

  • The role of aldose reductase in sugar cataract formation: aldose reductase plays a key role in lens epithelial cell death (apoptosis).

    abstract::Since aldose reductase is localized primarily in lens epithelial cells, osmotic insults induced by the accumulation of sugar alcohols occur first in these cells. To determine whether the accumulation of sugar alcohols can induce lens epithelial cell death, galactose-induced apoptosis has been investigated in dog lens ...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Murata M,Ohta N,Sakurai S,Alam S,Tsai J,Kador PF,Sato S

    更新日期:2001-01-30 00:00:00

  • Cadmium induces the activation of cell wall integrity pathway in budding yeast.

    abstract::MAP kinases are important signaling molecules regulating cell survival, proliferation and differentiation, and can be activated by cadmium stress. In this study, we demonstrate that cadmium induces phosphorylation of the yeast cell wall integrity (CWI) pathway_MAP kinase Slt2, and this cadmium-induced CWI activation i...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Xiong B,Zhang L,Xu H,Yang Y,Jiang L

    更新日期:2015-10-05 00:00:00

  • Effects of hypoxia and ethanol on xanthine oxidase of isolated rat hepatocytes: conversion from D to O form and leakage from cells.

    abstract::The combined effects of ethanol and hypoxia on the conversion of xanthine dehydrogenase (D form) to xanthine oxidase (O form) and on the leakage of the enzyme from isolated rat hepatocytes was studied. Time-dependent death of cells occurred during incubation in hypoxic conditions. Ethanol (40 mM) had only a moderate e...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Battelli MG,Abbondanza A,Stirpe F

    更新日期:1992-06-15 00:00:00

  • Influence of toluene co-exposure on the metabolism and genotoxicity of benzene in mice using continuous and intermittent exposures.

    abstract::Benzene exposure in occupational settings often occurs with concurrent exposure to toluene, the methyl-substituted derivative of benzene. Toluene is also readily metabolized by CYP450 isozymes although oxidation primarily occurs in the methyl group. While earlier mouse studies addressing co-exposure to benzene and tol...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Bird MG,Wetmore BA,Letinski DJ,Nicolich M,Chen M,Schnatter AR,Whitman FT

    更新日期:2010-03-19 00:00:00

  • Monoclonal antibodies to human butyrylcholinesterase reactive with butyrylcholinesterase in animal plasma.

    abstract::Five mouse anti-human butyrylcholinesterase (BChE) monoclonal antibodies bind tightly to native human BChE with nanomolar dissociation constants. Pairing analysis in the Octet system identified the monoclonal antibodies that bind to overlapping and independent epitopes on human BChE. The nucleotide and amino acid sequ...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Peng H,Brimijoin S,Hrabovska A,Krejci E,Blake TA,Johnson RC,Masson P,Lockridge O

    更新日期:2016-01-05 00:00:00

  • The metabolism and antitumour activity of the enantiomers of cis- and trans-4-methylcyclophosphamide.

    abstract::4-Methylcyclophosphamide, an analogue of the antitumour agent cyclophosphamide, exists in cis and trans forms, each of which comprises a pair of optical isomers. The extents of metabolism by rat liver microsomes during 20 min were compared for the four steroisomers incubated separately, and for the racemic cis and tra...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Farmer PB,Jarman M,Facchinetti T,Pankiewicz K,Stec WJ

    更新日期:1977-07-01 00:00:00

  • -116A and K BCHE gene variants associated with obesity and hypertriglyceridemia in adolescents from Southern Brazil.

    abstract::Butyrylcholinesterase (BChE) has been associated to body mass index (BMI), weight, cholesterol and triglyceride levels. -116A (rs1126680) and K (A539T, 1615A, rs1803274) BCHE gene variants had previously been associated to BChE activity, weight and BMI variance in adults. The present study examined -116A and K variant...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Chaves TJ,Leite N,Milano GE,Milano GE,Souza RL,Chautard-Freire-Maia EA,Furtado-Alle L

    更新日期:2013-03-25 00:00:00

  • Discovery of a series of aromatic lactones as ALDH1/2-directed inhibitors.

    abstract::In humans, the aldehyde dehydrogenase superfamily consists of 19 isoenzymes which mostly catalyze the NAD(P)(+)-dependent oxidation of aldehydes. Many of these isoenzymes have overlapping substrate specificities and therefore their potential physiological functions may overlap. Thus the development of new isoenzyme-se...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Buchman CD,Mahalingan KK,Hurley TD

    更新日期:2015-06-05 00:00:00

  • Cancer risk assessment for 1,3-butadiene: dose-response modeling from an epidemiological perspective.

    abstract::The dose-response assessment of the association between 1,3-butadiene (BD) and leukemia mortality among workers in the North American synthetic rubber industry is explored. Analyses are based on the most recent University of Alabama at Birmingham epidemiological study and exposure estimation. The U.S. EPA Science Advi...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Sielken RL Jr,Valdez-Flores C,Gargas ML,Kirman CR,Teta MJ,Delzell E

    更新日期:2007-03-20 00:00:00

  • Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats.

    abstract::The clinical use of doxorubicin is associated with dose limiting cardiotoxicity. This is a manifestation of free radical production triggered by doxorubicin. Therefore, we evaluated the efficacy of febuxostat, a xanthine oxidase inhibitor and antioxidant, in blocking cardiotoxicity associated with doxorubicin in rats....

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Krishnamurthy B,Rani N,Bharti S,Golechha M,Bhatia J,Nag TC,Ray R,Arava S,Arya DS

    更新日期:2015-07-25 00:00:00

  • Bioavailability and potential carcinogenicity of polycyclic aromatic hydrocarbons from wood combustion particulate matter in vitro.

    abstract::Due to increasing energy demand and limited fossil fuels, renewable energy sources have gained in importance. Particulate matter (PM) in general, but also PM from the combustion of wood is known to exert adverse health effects in human. These are often related to specific toxic compounds adsorbed to the PM surface, su...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Gauggel-Lewandowski S,Heussner AH,Steinberg P,Pieterse B,van der Burg B,Dietrich DR

    更新日期:2013-11-25 00:00:00

  • Template properties of DNA alkylated with N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea.

    abstract::Alkylation of DNA with N-methyl-N-nitrosourea (MeNU) and N-ethyl-N-nitrosourea (EtNU) reduces its ability to support RNA synthesis catalyzed by exogenously added RNA polymerase. It is likely that 7-alkylguanine and alkyl phosphotriester in DNA are mainly responsible for the inhibition of RNA synthesis. The inhibitory ...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Marushige K,Marushige Y

    更新日期:1983-09-01 00:00:00

  • Role of ELAV-like RNA-binding proteins HuD and HuR in the post-transcriptional regulation of acetylcholinesterase in neurons and skeletal muscle cells.

    abstract::Over the last few years, several laboratories have focused their attention on elucidating the molecular events that control the expression and localization of acetylcholinesterase (AChE) in neurons and skeletal muscle cells. In this context, results from a number of studies have clearly shown the important contributio...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Deschênes-Furry J,Angus LM,Bélanger G,Mwanjewe J,Jasmin BJ

    更新日期:2005-12-15 00:00:00

  • An in vitro model for evaluation of vaporous toxicity of trichloroethylene and tetrachloroethylene to CHO-K1 cells.

    abstract::Toxicokinetics of trichloroethylene (TCE) and tetrachloroethylene (PER) in culture medium and their toxicity to CHO-K1 cells were investigated by employing an in vitro vapor exposure system. Cells were cultured in a 60 mm petri dish with a 25 mm glass dish glued in the central area. TCE or PER was added to the central...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Wang JL,Chen WL,Tsai SY,Sung PY,Huang RN

    更新日期:2001-08-31 00:00:00

  • Inhibitory effects of antihypertensive drugs on human cytochrome P450 2J2 activity: Potent inhibition by azelnidipine and manidipine.

    abstract::The inhibitory effects of antihypertensive drugs (dihydropyridine calcium channel blockers, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors) on cytochrome P450 2J2 (CYP2J2) activity were examined. Amlodipine, azelnidipine, barnidipine, benidipine, cilnidipine, efonidipine, felodipine, ma...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Ikemura N,Yamaori S,Kobayashi C,Kamijo S,Murayama N,Yamazaki H,Ohmori S

    更新日期:2019-06-01 00:00:00

  • Platinum(II) complexes block the entry of T4 phage DNA into the host cells.

    abstract::The efficiency of multiplicity reactivation of T4 particles inactivated by platinum(II) complexes is very low. The same is true for marker rescue and functional survival of genes. This can be at least partly explained by the inability of most inactivated virus particles to introduce their DNA into the host cells as de...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Kerszman G,Josephsen J,Fernholm B

    更新日期:1979-12-01 00:00:00

  • Grandivittin as a natural minor groove binder extracted from Ferulago macrocarpa to ct-DNA, experimental and in silico analysis.

    abstract::Ferulago macrocarpa (Fenzl) Boiss., is an endemic medicinal herb of Iran. In this study a dihydrofuranocoumarin called grandivittin (GRA) was separate and purified from Ferulago macrocarpa (Fenzl) Boiss, and characterized by (1)H NMR and Mass spectroscopic methods. The electrochemical behavior of GRA was evaluated by ...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Ahmadi F,Valadbeigi S,Sajjadi SE,Shokoohinia Y,Azizian H,Taheripak G

    更新日期:2016-10-25 00:00:00

  • Targeting of acetylcholinesterase to lipid rafts of muscle.

    abstract::Despite the great progress made in setting the basis for the molecular diversity of acetylcholinesterase (AChE), an explanation for the existence of two types of amphiphilic subunits, with and without glicosylphosphatidylinositol (GPI) (Types I and II), has not been provided yet. In searching whether, as for the defic...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Moral-Naranjo MT,Montenegro MF,Muñoz-Delgado E,Campoy FJ,Vidal CJ

    更新日期:2008-09-25 00:00:00

  • Bis(12)-hupyridone, a novel acetylcholinesterase inhibitor, protects against glutamate-induced neuronal excitotoxicity via activating α7 nicotinic acetylcholine receptor/phosphoinositide 3-kinase/Akt cascade.

    abstract::Bis(12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor. In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate-induced neuronal excitotoxicity in cerebellar granule neurons (CGNs). Howev...

    journal_title:Chemico-biological interactions

    pub_type: 杂志文章


    authors: Cui W,Hu S,Chan HH,Luo J,Li W,Mak S,Choi TC,Rong J,Carlier PR,Han Y

    更新日期:2013-03-25 00:00:00