The β-adrenoceptor agonist isoproterenol promotes the activity of respiratory chain complex I and lowers cellular reactive oxygen species in fibroblasts and heart myoblasts

Rasmo, Domenico De; Gattoni, Giuliano; Papa, Francesco; Santeramo, Arcangela; Pacelli, Consiglia; Cocco, Tiziana; Micelli, Loris; Sardaro, Nicola; Larizza, Maria; Scivetti, Michele; Milano, Serena; Signorile, Anna

doi:10.1016/j.ejphar.2010.11.016

Cited by 34 publications

(32 citation statements)

References 34 publications

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“…This results in an increased functional capacity of respiratory chain complexes, in particular complex I, which, under various conditions, seems to be the pacemaker of the mitochondrial respiratory activity De Rasmo et al, 2011). These observations thus provide further direct evidence that mitochondrial energy supply is critical for the development of brain regions and their functionality.…”

Section: Discussionsupporting

confidence: 49%

Rat Embryo Exposure to All-Trans Retinoic Acid Results in Postnatal Oxidative Damage of Respiratory Complex I in the Cerebellum

Signorile

Sardaro²,

Rasmo³

et al. 2011

Mol Pharmacol

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The results of the present work show that the exposure of pregnant rats to low doses of all-trans-retinoic acid (ATRA) (2.5 mg/kg body weight) results in postnatal dysfunction of complex I of the respiratory chain in the cerebellum of the offspring. ATRA had no effect on the postnatal expression of complex I and did not exert any direct inhibitory effect on the enzymatic activity of the complex. The ATRA embryonic exposure resulted, however, in a marked increase in the level of carbonylated proteins in the mitochondrial fraction of the cerebellum, in particular of complex I subunits. The postnatal increase of the carbonylated proteins correlated directly with the inhibition of the activity of complex I. ATRA had, on the other hand, no effect on oxygen free-radical scavengers. It is proposed that embryonic exposure to ATRA results in impairment of protein surveillance in the cerebellum, which persists after birth and results in accumulation of oxidatively damaged complex I.

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Section: Discussionsupporting

confidence: 49%

Rat Embryo Exposure to All-Trans Retinoic Acid Results in Postnatal Oxidative Damage of Respiratory Complex I in the Cerebellum

Signorile

Sardaro²,

Rasmo³

et al. 2011

Mol Pharmacol

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“…The probe fluorescence intensity (507 nm excitation and 530 nm emission wavelengths) was measured by a Jasco FP6200 spectrofluorimeter (see also ref. [17]). …”

Section: Cell Culturesmentioning

confidence: 93%

“…Previous work from our laboratory has shown that addition to cell cultures of the membrane permeant derivate of cAMP, 8-Br-cAMP (8-bromoadenosine 3′,5′-cyclic monophosphate), and, equally effective, activation of transmembrane adenylyl cyclase (tmAC) by cholera toxin [16] or the β-adrenoceptor agonist, isoproterenol [17], rescue the depression of complex I activity and the increase in cellular ROS level observed in murine and human fibroblast cultures in the G0 phase [18] and in oxidatively damaged cell cultures [8]. Other investigations showed that phosphorylation by extramitochondrial PKA of serine in the C-terminus RVS conserved site of the nuclear-encoded NDUFS4 subunit of complex I [19,20] promotes mitochondrial import and maturation of the precursor form of the protein and prevents retrograde back diffusion in the cytosol of the mature form of the protein [21].…”

Section: Introductionmentioning

confidence: 99%

Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Rasmo¹,

Signorile²,

Santeramo³

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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In mammalian cells the nuclear-encoded subunits of complex I are imported into mitochondria, where they are assembled with mt-DNA encoded subunits in the complex, or exchanged with pre-existing copies in the complex. The present work shows that in fibroblast cultures inhibition by KH7 of cAMP production in the mitochondrial matrix by soluble adenylyl cyclase (sAC) results in decreased amounts of free non-incorporated nuclear-encoded NDUFS4, NDUFV2 and NDUFA9 subunits of the catalytic moiety and inhibition of the activity of complex I. Addition of permeant 8-Br-cAMP prevents this effect of KH7. KH7 inhibits accumulation in isolated rat-liver mitochondria and incorporation in complex I of "in vitro" produced, radiolabeled NDUFS4 and NDUFV2 subunits. 8-Br-cAMP prevents also this effect of KH7. Use of protease inhibitors shows that intramitochondrial cAMP exerts this positive effect on complex I by preventing digestion of nuclear-encoded subunits by mitochondrial protease(s), whose activity is promoted by KH7 and H89, an inhibitor of PKA.

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“…The ATP production rate was then calculated from this O 2 flux using the phosphorus/oxygen ratio (P/O ratio). The latter was determined by measuring the amount of O 2 required to convert 220 nmol ADP to ATP in permeabilized cells supplemented with PYR and malate (50). This strategy revealed a P/O ratio of 2.7 5 0.4 (SD) ( Table 1, B3; Fig.…”

Section: Model Predictions Of Steady-state Atp Productionmentioning

confidence: 99%

Mitoenergetic Dysfunction Triggers a Rapid Compensatory Increase in Steady-State Glucose Flux

Liemburg-Apers

Schirris

Rüssel

et al. 2015

Biophysical Journal

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ATP can be produced in the cytosol by glycolytic conversion of glucose (GLC) into pyruvate. The latter can be metabolized into lactate, which is released by the cell, or taken up by mitochondria to fuel ATP production by the tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) system. Altering the balance between glycolytic and mitochondrial ATP generation is crucial for cell survival during mitoenergetic dysfunction, which is observed in a large variety of human disorders including cancer. To gain insight into the kinetic properties of this adaptive mechanism we determined here how acute (30 min) inhibition of OXPHOS affected cytosolic GLC homeostasis. GLC dynamics were analyzed in single living C2C12 myoblasts expressing the fluorescent biosensor FLII(12)Pglu-700μδ6 (FLII). Following in situ FLII calibration, the kinetic properties of GLC uptake (V1) and GLC consumption (V2) were determined independently and used to construct a minimal mathematical model of cytosolic GLC dynamics. After validating the model, it was applied to quantitatively predict V1 and V2 at steady-state (i.e., when V1 = V2 = Vsteady-state) in the absence and presence of OXPHOS inhibitors. Integrating model predictions with experimental data on lactate production, cell volume, and O2 consumption revealed that glycolysis and mitochondria equally contribute to cellular ATP production in control myoblasts. Inhibition of OXPHOS induced a twofold increase in Vsteady-state and glycolytic ATP production flux. Both in the absence and presence of OXPHOS inhibitors, GLC was consumed at near maximal rates, meaning that GLC consumption is rate-limiting under steady-state conditions. Taken together, we demonstrate here that OXPHOS inhibition increases steady-state GLC uptake and consumption in C2C12 myoblasts. This activation fully compensates for the reduction in mitochondrial ATP production, thereby maintaining the balance between cellular ATP supply and demand.

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The β-adrenoceptor agonist isoproterenol promotes the activity of respiratory chain complex I and lowers cellular reactive oxygen species in fibroblasts and heart myoblasts

Cited by 34 publications

References 34 publications

Rat Embryo Exposure to All-Trans Retinoic Acid Results in Postnatal Oxidative Damage of Respiratory Complex I in the Cerebellum

Rat Embryo Exposure to All-Trans Retinoic Acid Results in Postnatal Oxidative Damage of Respiratory Complex I in the Cerebellum

Intramitochondrial adenylyl cyclase controls the turnover of nuclear-encoded subunits and activity of mammalian complex I of the respiratory chain

Mitoenergetic Dysfunction Triggers a Rapid Compensatory Increase in Steady-State Glucose Flux

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