Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

Nisoli, Enzo; Falcone, Sestina; Tonello, Cristina; Cozzi, Valeria; Palomba, Letizia; Fiorani, Mara; Pisconti, Addolorata; Brunelli, Silvia; Cardile, Annalisa; Francolini, Maura; Cantoni, Orazio; Carruba, Michele O.; Moncada, Salvador; Clementi, Emilio

doi:10.1073/pnas.0405432101

Cited by 462 publications

(426 citation statements)

References 52 publications

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“…On this basis, mitochondrial function and cellular respiration would be expected to increase in the condition of low NO in IPAH. However, NO also has other long-term effects on mitochondrial biogenesis and function in cells (14)(15)(16)(17), e.g., NO/cGMP-dependent mitochondrial biogenesis is associated with enhanced coupled respiration, oxygen consumption, and ATP content (14)(15)(16)(17). Here, decreased mitochondria functional activities in the context of preserved respiratory control index in IPAH cells suggested that decreased activity was not due to mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…For example, eNOS-deficient mice, which have mild pulmonary hypertension under normoxia and an exaggerated pulmonary vasoconstrictive response to hypoxia (18), have reduced mitochondria content in a wide range of tissues in association with significantly lower oxygen consumption and ATP content (14)(15)(16)(17). Mitochondria are essential to cellular energy production in all higher organisms adapted to an oxygen-containing environment, i.e., ATP produced through oxidative phosphorylation.…”

Section: Idiopathic Pulmonary Arterial Hypertension (Ipah) Is Pathogementioning

confidence: 99%

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Alterations of cellular bioenergetics in pulmonary artery endothelial cells

Koeck

Lara

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

358

402

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Idiopathic pulmonary arterial hypertension (IPAH) is pathogenetically related to low levels of the vasodilator nitric oxide (NOcellular respiration ͉ nitric oxide ͉ oxygen consumption ͉ pulmonary hypertension ͉ mitochondrion I diopathic pulmonary arterial hypertension (IPAH) is a fatal disease of unknown etiology characterized by a progressive increase in pulmonary artery pressure and vascular growth (1, 2). Secondary forms of pulmonary arterial hypertension (PAH) are associated with known diseases, such as collagen vascular diseases or portal hypertension but in the absence of an identifiable etiology are classified as IPAH. Abnormalities in vasodilators, specifically nitric oxide (NO), have been implicated in the pathogenesis of pulmonary hypertension (1-5). NO is produced in the lung by NO synthases (NOS; EC 1.14.13.39) (6-8). There is conclusive evidence from animal models of pulmonary hypertension, mice genetically deficient in endothelial NOS (eNOS), and complementation studies with gene transfer of NOSs for the concept that NO is a critical determinant of pulmonary vascular tone (6, 7, 9). Furthermore, pulmonary and total body NO are lower in IPAH patients as compared with healthy controls (3,(10)(11)(12), and the decrease of NO has been linked to increased arginase II and decreased eNOS expression in IPAH pulmonary endothelial cells in vivo (10,13).In addition to effects on vascular tone, NO regulates cellular bioenergetics through effects on glycolysis, oxygen consumption by mitochondrion, and mitochondrial biogenesis (14-17). For example, eNOS-deficient mice, which have mild pulmonary hypertension under normoxia and an exaggerated pulmonary vasoconstrictive response to hypoxia (18), have reduced mitochondria content in a wide range of tissues in association with significantly lower oxygen consumption and ATP content (14-17). Mitochondria are essential to cellular energy production in all higher organisms adapted to an oxygen-containing environment, i.e., ATP produced through oxidative phosphorylation. The electrochemical gradient used by mitochondrial F 0 F 1 ATP synthase to synthesize ATP from ADP is generated by the proton pump action performed by Complexes I, III, and IV of the respiratory chain. The proton pumping is accompanied by electron shuttling, whereby Complexes I and II, along with the flavoprotein-ubiquinone oxidoreductase, transfer electrons from different sources to ubiquinone (coenzyme Q). The electrons are then transferred sequentially to Complex III, cytochrome c, Complex IV, and finally to molecular oxygen, the terminal electron acceptor. All multisubunit complexes of the respiratory chain (I-IV) are located in the mitochondrial inner membrane. Thus, mitochondria are the primary oxygen demand in the body, accounting for Ϸ90% of cellular oxygen consumption. Conversely, under limiting oxygen conditions, cells turn to glycolysis to generate energy. In endothelial cells, ATP is generated nearly equivalently by glycolysis and cellular respiration (19), accounting for a relative tolerance ...

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Section: Discussionmentioning

confidence: 99%

Section: Idiopathic Pulmonary Arterial Hypertension (Ipah) Is Pathogementioning

confidence: 99%

Alterations of cellular bioenergetics in pulmonary artery endothelial cells

Koeck

Lara

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

358

402

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“…CO also has endogenous signaling properties, for instance, in the vasculature, where it relaxes smooth muscle by activating soluble guanylate cyclase (sGC), which is similar to but less potent than NO (13). Moreover, the eNOS-sGC system regulates mitochondrial biogenesis (14,15), as does CO, also in part via sGC, but independently of eNOS (16). CO further binds the reduced a 3 heme of cytochrome c oxidase (COX), which enhances mitochondrial H 2 O 2 release and contributes to retrograde activation of the nuclear mitochondrial biogenesis program via binding of the nuclear respiratory factor 1 (NRF-1) transcription factor with the PGC-1α coactivator to target genes (16,17).…”

Section: Introductionmentioning

confidence: 99%

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

Suliman¹,

Carraway²,

Ali³

et al. 2007

J. Clin. Invest.

180

243

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The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.

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“…Guanosine monophosphate (cGMP) signalling appears to be an important pathway by which NO induces PGC-1α expression. Indeed, in similar fashion to NO donors, cGMP analogues have shown to increase the mRNA expression of PGC-1α and other mitochondrial transcription factors and proteomes (Nisoli et al, 2004). In addition, pharmacologically inhibiting cGMP synthesis abolished these effects, highlighting the important role of cGMP in NO induced PGC-1α expression (Nisoli et al, 2004).…”

Section: Nitric Oxidementioning

confidence: 99%

“…For instance, treatment with NO donors has shown to increase the mRNA expression of PGC-1α, NRF1 and Tfam and several other respiratory chain components in muscle cell cultures (Nisoli et al, 2004). In addition, eNOS deficient mice have shown to have reduced mitochondrial density when compared with wild-type controls (Nisoli et al, 2004). Guanosine monophosphate (cGMP) signalling appears to be an important pathway by which NO induces PGC-1α expression.…”

Section: Nitric Oxidementioning

confidence: 99%

PGC-1α Mediated Muscle Aerobic Adaptations to Exercise, Heat and Cold Exposure

Ihsan¹,

Watson²,

Abbiss³

2014

Cell Mol Exerc Physiol

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PGC-1α is regarded as a key regulator of mitochondrial biogenesis due to its central role in regulating the activity of key transcription factors associated with encoding mitochondrial components. Additionally, PGC-1α has shown to mediate adaptations that increase fat metabolism and angiogenesis, contributing to the overall oxidative phenotype of the muscle. While it is well established that exercise is a potent stimulator of PGC-1α, recent evidence indicates that heat and cold exposures may also influence mitochondrial biogenesis through the up-regulation of PGC-1α. This highlights the potential use of these modalities in conjunction with exercise to enhance training adaptations. As such, the purpose of this review is to describe the possible mechanisms and pathways by which exercise, as well as hot and cold exposures may influence mitochondrial biogenesis. It is clear that changes in intracellular calcium, oxidative stress and phosphorylation potential are major up-regulators of PGC-1α during exercise. Moreover, there is evidence implicating calcium signalling, in addition to β-adrenergic activation in cold-induced mitochondrial biogenesis, while PGC-1α during heat exposure is likely triggered by changes in phosphorylation potential and nitric oxide signalling. However, these mechanisms appear to change considerably when cold/heat is administered following exercise, and seem to be dependent on the experimental models used (i.e. in vitro vs. in vivo, rodent vs. human). Understanding the effects heat/cold exposure and its interaction with exercise may lead to the optimisation and development of temperature-related interventions to enhance training adaptations, or aid in the treatment of mitochondrial related diseases.

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Mitochondrial biogenesis by NO yields functionally active mitochondria in mammals

Cited by 462 publications

References 52 publications

Alterations of cellular bioenergetics in pulmonary artery endothelial cells

Alterations of cellular bioenergetics in pulmonary artery endothelial cells

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy

PGC-1α Mediated Muscle Aerobic Adaptations to Exercise, Heat and Cold Exposure

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