Giorgio Lenaz's research while affiliated with University of Bologna and other places

Publications (451)

Article
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Mitochondria are the powerhouses of cells; however, mitochondrial dysfunction causes energy depletion and cell death in various diseases [...]
Article
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Under aerobic conditions, mitochondrial oxidative phosphorylation (OXPHOS) converts the energy released by nutrient oxidation into ATP, the currency of living organisms. The whole biochemical machinery is hosted by the inner mitochondrial membrane (mtIM) where the protonmotive force built by respiratory complexes, dynamically assembled as super-com...
Chapter
In this chapter we provide a review with a focus on the function of Coenzyme Q (CoQ, ubiquinone) in mitochondria. The notion of a mobile pool of CoQ in the lipid bilayer as the vehicle of electrons from respiratory complexes has somewhat changed with the discovery of respiratory supramolecular units, in particular the supercomplex comprising Comple...
Chapter
The reversible oxidation of dihydroxy arenes to the respective quinones is a two-electron process with the intermediate formation of the radical form of semiquinones. The redox systems quinone/diphenol (or quinol) are widely present in nature; they participate in electron transfer chains of eukaryotic cells and bacteria, and are involved in the ant...
Preprint
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Mitochondrial respiratory states and rates MitoEAGLE Task Group
Article
It was discovered over 60 years ago that the mitochondrial respiratory chain is constituted of a series of protein complexes imbedded in the inner mitochondrial membrane. Experimental evidence has more recently ascertained that the major respiratory complexes involved in energy conservation are assembled as supramolecular units (supercomplexes, SCs...
Article
Familial aggregation is a significant risk factor for the development of thyroid cancer and Familial Non‐Medullary Thyroid Cancer (FNMTC) accounts for 5‐7% of all NMTC. Whole Exome Sequencing analysis in the family affected by FNMTC with oncocytic features where our group previously identified a predisposing locus on chromosome 19p13.2, revealed a...
Conference Paper
Mitochondria are both the cellular powerhouse and the major source of reactive oxygen species. These functions are performed by the mitochondrial electron transfer chain in which Coenzyme Q10 plays a key role. In addition, CoQ has also been found to have an antioxidant function. For these reasons it can be argued that modifications of physiological...
Chapter
Evidence from several investigations demonstrates the existence of supramolecular units of Complex I, Complex III, and multiple copies of Complex IV in mitochondria and indicates that specific respiratory complexes may preferentially associate to form cytochrome-containing supercomplexes in the native membrane. There are now indications thatcardiol...
Article
This review discusses the functional properties of mitochondrial Complex I originating from its presence in an assembled form as a supercomplex comprising Complex III and Complex IV in stoichiometric ratios. In particular several lines of evidence are presented favoring the concept that electron transfer from Complex I to Complex III is operated by...
Article
The molecular mechanism of aging is still vigorously debated, although a general consensus exists that mitochondria are significantly involved in this process. However, the previously postulated role of mitochondria-derived reactive oxygen species (ROS) as the damaging agents inducing functional loss in aging has fallen out of favour in the recent...
Article
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Despite more than 50 years of investigations into the free radical theory, the direct role of oxidative stress (OS) in aging and age-related diseases remains unproven. Little progress in identifying antioxidant drugs promoting longevity has been made, likely due to selectivity toward one or few radical species, variable efficacy in vivo, inherent p...
Article
Two alternative models of organization of the mitochondrial electron transport chain (mETC) have been alternatively favored or questioned by the accumulation evidences of different sources, the solid model or the random collision model. Both agree in the number of respiratory complexes (I-IV) that participate in the mETC, but while the random colli...
Article
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Mitochondria have been considered for long time as important determinants of cell aging because of their role in the production of reactive oxygen species. In this study we investigated the impact of mitochondrial metabolism and biology as determinants of successful aging in primary cultures of fibroblasts isolated from the skin of long living indi...
Article
Recent experimental evidence has replaced the random diffusion model of electron transfer with a model of supramolecular organisation based upon specific interactions between individual respiratory complexes. These supercomplexes were found to be functionally relevant by flux control analysis and to confer a kinetic advantage to NAD-linked respirat...
Article
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Aims: The mitochondrial respiratory chain is recognized today to be arranged in supramolecular assemblies (supercomplexes). Besides conferring a kinetic advantage (substrate channeling) and being required for the assembly and stability of Complex I, indirect considerations support the view that supercomplexes may also prevent excessive formation o...
Article
Abstract Substantial evidence exists that the mitochondrial respiratory chain is organized in supramolecular units called supercomplexes or respirasomes. While the structural evidence of the supercomplexes is overwhelming, fewer studies were addressed to their functional relevance. Although the presence of Coenzyme Q channelling between Complexes I...
Chapter
The reversible oxidation of dihydroxyarenes to the respective quinones is a two-electron process with the intermediate formation of the radical form of semiquinones. The redox systems quinone/diphenol (or quinol) are widely present in nature; they participate in electron transfer chains of eukaryotic cells and bacteria, and are involved in the anti...
Article
Cancer cells are characterized in general by a decrease of mitochondrial respiration and oxidative phosphorylation, together with a strong enhancement of glycolysis, the so-called Warburg effect. The decrease of mitochondrial activity in cancer cells may have multiple reasons, related either to the input of reducing equivalents to the electron tran...
Data
Effect of B6 addition on ROS production by respiring bovine heart submitochondrial particles. Data were obtained evaluating the DCFDA fluorescence after 1 hour in presence and absence of B6. B6 effect on the ROS production in SMP is compared with ROS production induced by 2 µM rotenone. (PPTX)
Data
Results from protein analysis by LC/ESI/MS/MS-QTOF after direct tryptic digestion of affinity and control matrices. LC separation using two different gradients (gradient A and B) and subsequent mass spectrometry and database searches provided with the probability of 95% for trypanosome proteins that were absent in the control matrix (ac) but were p...
Data
B6 effect on NADH-O2 and succinate-O2 activity in bovine heart submitochondrial particles (SMP). O2 consumption in SMP (40 µg/ml) was induced by addition of 150 µM NADH or 10 mM of succinate in the presence and in the absence of 20 µM of B6. (PPTX)
Article
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Recently, we reported on a new class of naphthoquinone derivatives showing a promising anti-trypanosomatid profile in cell-based experiments. The lead of this series (B6, 2-phenoxy-1,4-naphthoquinone) showed an ED(50) of 80 nM against Trypanosoma brucei rhodesiense, and a selectivity index of 74 with respect to mammalian cells. A multitarget profil...
Article
Recent experimental evidence has replaced the random diffusion model of electron transfer with a model of supramolecular organisation based on specific interactions between individual respiratory complexes. These supercomplexes are detected by blue-native electrophoresis and are found to be functionally relevant by flux control analysis; moreover,...
Article
Full-text available
Mitochondria are both the cellular powerhouse and the major source of reactive oxygen species. Coenzyme Q(10) plays a key role in mitochondrial energy production and is recognized as a powerful antioxidant. For these reasons it can be argued that higher mitochondrial ubiquinone levels may enhance the energy state and protect from oxidative stress....
Article
Oxidative stress is among the major causes of toxicity due to interaction of Reactive Oxygen Species (ROS) with cellular macromolecules and structures and interference with signal transduction pathways. The mitochondrial respiratory chain, specially from Complexes I and III, is considered the main origin of ROS particularly under conditions of high...
Article
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Liver ischemia-reperfusion injury is still an open problem in many clinical circumstances, including surgery and transplantation. This study investigates how mitochondrial structure, mass and oxidative phosphorylation change and may be preserved during a brief period of ischemia followed by a long period of reperfusion, an experimental model that m...
Article
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We have studied the effects of idebenone on mitochondrial function in cybrids derived from one normal donor (HQB17) and one patient harboring the G3460A/MT-ND1 mutation of Leber's Hereditary Optic Neuropathy (RJ206); and in XTC.UC1 cells bearing a premature stop codon at amino acid 101 of MT-ND1 that hampers complex I assembly. Addition of idebenon...
Article
The notion of a mobile pool of coenzyme Q (CoQ) in the lipid bilayer has changed with the discovery of respiratory supramolecular units, in particular the supercomplex comprising complexes I and III; in this model, the electron transfer is thought to be mediated by tunneling or microdiffusion, with a clear kinetic advantage on the transfer based on...
Article
The localization of ubiquinone has been investigated in phospholipid bilayer vesicles in studies of fluorescence quenching of membrane-bound probes by ubiquinone homologs (Qn, where n is the number of the isoprenoid units of the chain). Fluorescence-quenching data obtained by using a set of anthroylstearate probes, having the fluorophore located at...
Article
Mitochondria-directed antioxidants 2-5 were designed by conjugating curcumin congeners with different polyamine motifs as vehicle tools. The conjugates emerged as efficient antioxidants in mitochondria and fibroblasts and also exerted a protecting role through heme oxygenase-1 activation. Notably, the insertion of a polyamine function into the curc...
Article
Although the role of STAT3 in cell physiology and tissue development has been largely investigated, its involvement in the development and maintenance of nervous tissue and in the mechanisms of neuroprotection is not yet known. The potentially wide range of STAT3 activities raises the question of tissue- and gender-specificity as putative mechanism...
Article
Recent investigations by native gel electrophoresis showed the existence of supramolecular associations of the respiratory complexes, confirmed by electron microscopy analysis and single particle image processing. Flux control analysis demonstrated that Complex I and Complex III in mammalian mitochondria kinetically behave as a single unit with con...
Article
Pyrethroids are one of the most widely used class of insecticides and their toxicity is dominated by pharmacological actions upon the CNS. This study reports as the subchronic treatment (60 days) with permethrin (PERM) (1/10 of LD(50)) induced nuclear DNA damage in rat striatum cells. Comet assay outcomes showed that PERM produced single- and doubl...
Article
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Following experimental hind limb denervation in rats, this study demonstrates that oxidative stress occurs and advances an hypothesis about its origin. In fact: (i) ROS are formed; (ii) membrane lipids are oxidized; (iii) oxidized ion channels and pumps may lead to increased [Ca(2+)](i); all the above mentioned events increase with denervation time...
Article
It is now clear that mitochondrial defects are associated with a large variety of clinical phenotypes. This is the result of the mitochondria's central role in energy production, reactive oxygen species homeostasis, and cell death. These processes are interdependent and may occur under various stressing conditions, among which low oxygen levels (hy...
Chapter
Oxidative stress is among the major causes of toxicity due to interaction of reactive oxygen species (ROS) with cellular macromolecules and structures and interference with signal transduction pathways. ROS originate from exogenous and endogenous sources; among the former are UV and ionizing radiation and xenobiotics, the latter are represented by...
Article
Metabolic control analysis was applied to intact HepG2 cells. The effect on the control coefficient of cytochrome c oxidase (CcOX) over cell respiration of both the electrical (Δψ) and chemical (ΔpH) component of the mitochondrial transmembrane proton electrochemical gradient (ΔμH+) was investigated. The overall O2 consumption and specific CcOX act...
Article
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Many cancer cells are characterized by high rate of glycolysis and reduced rate of aerobic respiration, whose mechanism is still elusive. Here we investigate the down-regulation of oxidative phosphorylation (OXPHOS) in K-ras transformed mouse fibroblasts as compared to a control counterpart. Transcriptional analysis showed different expression leve...
Article
The structural organization of the mitochondrial oxidative phosphorylation (OXPHOS) system has received large attention in the past and most investigations led to the conclusion that the respiratory enzymatic complexes are randomly dispersed in the lipid bilayer of the inner membrane and functionally connected by fast diffusion of smaller redox com...
Article
The enzymatic complexes of the mitochondrial respiratory chain have been extensively investigated in their structural and functional properties. A clear distinction is possible today between three complexes in which the difference in redox potential allows proton translocation (complexes I, III, and IV) and those having the mere function to convey...
Article
Coenzyme Q (ubiquinone, CoQ<sub>10</sub>) is an essential electron carrier in the mitochondrial respiratory chain. It is located mainly in the inner mitochondrial membrane, but is also present in serum lipoproteins, endomembranes and the plasma membrane of eukaryotic cells (Turunen et al. 2004). CoQ<sub>10</sub> is also a redox component of electro...
Article
Novel multitargeted antioxidants 3-6 were designed by combining the antioxidant features, namely, a benzoquinone fragment and a lipoyl function, of two multifunctional lead candidates. They were then evaluated to determine their profile against Alzheimer's disease. They showed antioxidant activity, improved following enzymatic reduction, in mitocho...
Article
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To verify whether enhanced substrate-level phosphorylation increases viability and adenosine 5'-triphosphate (ATP) content of cells with neuropathy, ataxia, and retinitis pigmentosa/maternally inherited Leigh syndrome (NARP/MILS) mitochondrial DNA mutations and ATP synthase dysfunction. We used cell lines "poisoned" with oligomycin, the specific in...
Article
Full-text available
Metabolic control analysis was applied to intact HepG2 cells. The effect on the control coefficient of cytochrome c oxidase (CcOX) over cell respiration of both the electrical (Delta psi) and chemical (Delta pH) component of the mitochondrial transmembrane proton electrochemical gradient (Delta mu(H(+))) was investigated. The overall O(2) consumpti...
Article
Full-text available
Objective: To verify whether enhanced substrate-level phosphorylation increases viability and adenosine 5'-triphosphate (ATP) content of cells with neuropathy, ataxia, and retinitis pigmentosa/maternally inherited Leigh syndrome (NARP/MILS) mitochondrial DNA mutations and ATP synthase dysfunction. Design: We used cell lines "poisoned" with oligomyc...
Article
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The knowledge of coenzyme Q levels in tissues, organs, and subcellular compartments is of outstanding interest. A wide amount of data regarding coenzyme Q distribution and occurrence was collected in the last decades; nevertheless the data are often hard to compare because of the different extraction methods and different analytical techniques used...
Article
This investigation shows the effect of a Ca2+ addition on the structural and physicochemical properties of microvillus plasma membranes obtained from human placenta. Ca2+ addition induces an increase in microviscosity, as shown by the increase of order parameter and rotational correlation time of 5-and 16-doxylsterate derivatives and by the increas...
Article
Alpha-bisabolol is a natural monocyclic sesquiterpene alcohol. It has been used in cosmetics for hundreds of years because of its perceived skin-healing properties. Alpha-bisabolol is known to have anti-irritant, anti-inflammatory and antimicrobial properties. In precedent studies, we described how alpha-bisabolol exerts a selective pro-apoptotic a...
Article
The kinetic analysis by Kröger and Klingenberg on electron transfer in the Coenzyme Q region led to the conclusion that the quinone behaves kinetically as a homogeneous pool freely diffusing in the lipid bilayer, thus setting the basis for the widely accepted random diffusion model of electron transfer. The recent description of supramolecular comp...
Article
We have investigated the production of reactive oxygen species (ROS) by Complex I in isolated open bovine heart submitochondrial membrane fragments during forward electron transfer in presence of NADH, by means of the probe 2',7'-Dichlorodihydrofluorescein diacetate. ROS production by Complex I is strictly related to its inhibited state. Our result...
Article
Mitochondrial F(1)F(0)-ATPase was studied in lymphocytes from patients with neuropathy, ataxia, and retinitis pigmentosa (NARP), caused by a mutation at leu-156 in the ATPase 6 subunit. The mutation giving the milder phenotype (Leu156Pro) suffered a 30% reduction in proton flux, and a similar loss in ATP synthetic activity. The more severe mutation...
Article
The supra-molecular assembly of the main respiratory chain enzymatic complexes in the form of "super-complexes" has been proved by structural and functional experimental evidence. This evidence strongly contrasts the previously accepted Random Diffusion Model stating that the complexes are functionally connected by lateral diffusion of small redox...
Article
Mitochondrial Complex I [NADH Coenzyme Q (CoQ) oxidoreductase] is the least understood of respiratory complexes. In this review we emphasize some novel findings on this enzyme that are of relevance to the pathogenesis of neurodegenerative diseases. Besides CoQ, also oxygen may be an electron acceptor from the enzyme, with generation of superoxide r...
Article
Idebenone (IDE), a synthetic analog of coenzyme Q, strongly activates glycerol phosphate (GP) oxidation in brown adipose tissue mitochondria. GP oxidase, GP cytochrome c oxidoreductase and GP dehydrogenase activities were all significantly stimulated by 13 muM IDE. Substituted derivatives of IDE acetyl- and methoxyidebenone had similar activating e...
Chapter
AbbreviationsIntroductionMolecular Structure of Membrane Bound EnzymesSidedness and Topography of Membrane EnzymesIsolation and Reconstitution of Membrane EnzymesConsequences of Membrane BindingRole of Lipids in Membrane Bound EnzymesDetermination of the Kinetic Constants of Enzymes with Hydrophobic SubstratesKinetics of Membrane Bound Versus Solub...
Article
Mitochondrial reactive oxygen species (ROS) are mainly produced by the respiratory chain enzymes. The sites for ROS production in mitochondrial respiratory chain are normally ascribed to the activity of Complex I and III. The presence of specific inhibitors modulates reactive oxygen species production in Complex I: inhibitors such as rotenone induc...
Article
Despite enormous scientific and economic effort tumour still is one of the most terrible pathologies among human population all over the world. Products derived from the plant kingdom have often offered an opportunity to counteract or alleviate this illness. Here, we summarize the short story of the study of an extraordinary effect of one plant com...