Nucleus-encoded regulators of mitochondrial function: Integration of respiratory chain expression, nutrient sensing and metabolic stress

Scarpulla, Richard C.

doi:10.1016/j.bbagrm.2011.10.011

Cited by 138 publications

(116 citation statements)

References 150 publications

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“…For instance, PGC-1α also coactivates the nuclear respiratory factors NRF-1 and NRF-2 (60, 64). NRF-1 and -2 activate expression of multiple respiratory chain subunits in addition to the mitochondrial transcription factor TFAM (65)(66)(67). This latter circuit provides one mechanism for the coordinate control of nuclear and mitochondrial genomes.…”

Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 99%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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The adult mammalian heart has immense energy demands in order to support its role as a constantly active pump. Indeed, the human heart generates and utilizes kilogram quantities of ATP each day. The vast majority of ATP produced in the cardiac myocyte is generated via oxidative phosphorylation (OXPHOS) within a very-high-capacity mitochondrial system. The heart must continually adapt to changing physiologic conditions that influence workload, as well as alterations in oxygen and energy substrate availability. Notably, given that the heart has a limited capacity for fuel storage, it must utilize several energy substrates in an efficient and dynamic manner. As will be described, members of the nuclear receptor transcription factor superfamily serve to dynamically control preference and capacity for cardiac mitochondrial fuel metabolism during development and in response to myriad physiologic conditions. In addition, alterations in nuclear receptor signaling occur with pathologic cardiac growth and remodeling en route to heart failure.The adult cardiac myocyte has a higher density of mitochondria than any other cell type (1). The biogenesis of this highcapacity mitochondrial system occurs largely during the perinatal stage of development. This process involves a major burst of mitochondrial biogenesis at birth, followed by a period of mitochondrial maturation and remodeling during the postnatal period (2). Recent evidence indicates that postnatal mitochondrial maturation involves highly coordinated events including mitophagy, biogenesis, and dynamics (fusion and fission), resulting in a mitochondria network that is densely packed between sarcomeres to directly supply ATP to support cardiac contraction (2). The adult cardiac mitochondria are equipped with enzymatic machinery capable of oxidizing multiple substrates including fatty acids (the chief fuel) as well as glucose (pyruvate) and ketone bodies. This mitochondrial developmental maturation process occurs in parallel with well-characterized changes in the expression of contractile apparatus isoforms, ion channels, and calcium handling proteins. The collective perinatal programming in energy metabolic and structural genes results in an efficient and enduring pump for the adult life of the organism.The postnatal heart has an amazing capacity to oxidize multiple fuels and, therefore, is "omnivorous." Pioneering work by multiple groups has defined dynamic shifts in fuel utilization capacity and preferences during development and in disease states. The fetal and immediate postnatal heart relies primarily on glucose (glycolysis) and lactate as energy sources (3-5). However, very soon after birth the heart shifts to fatty acids as the major fuel substrate, coincident with the mitochondrial biogenic response (Figure 1 and refs. 5-8). The level of glucose oxidation also increases (8). The postnatal heart is also capable of oxidizing ketones, albeit at a low level, concomitant with the postnatal rise in circulating ketones (5). The shifts in fuel preference after birth ar...

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Section: Control Of Cardiac Mitochondrial Biogenesis and Dynamics: Thmentioning

confidence: 99%

Cardiac nuclear receptors: architects of mitochondrial structure and function

Vega¹,

Kelly²

2017

Journal of Clinical Investigation

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“…19 In addition, mitochondrial DNA, which codes for 13 essential electron transport chain proteins, is prone to oxidative stress. 20 Therefore, oxidative stresseinduced damage of mitochondrial DNA often leads to impaired transcription of electron transport chain proteins, which compromises electron transport chain function and further escalates ROS production. 20,21 In addition, the inhibition of superoxides also inhibited glucose-induced release of proapoptotic cytochrome c and Bax in retinal pericytes and endothelial cells, thus further substantiating a causal link between mitochondrial oxidative stress and DR pathogenesis.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

“…20 Therefore, oxidative stresseinduced damage of mitochondrial DNA often leads to impaired transcription of electron transport chain proteins, which compromises electron transport chain function and further escalates ROS production. 20,21 In addition, the inhibition of superoxides also inhibited glucose-induced release of proapoptotic cytochrome c and Bax in retinal pericytes and endothelial cells, thus further substantiating a causal link between mitochondrial oxidative stress and DR pathogenesis. 22 Altered Levels of Nox NADPH oxidase (Nox) enzymes catalyze the oxidation of NADPH to NADP in the cytosol and the reduction of oxygen across biological membranes to generate superoxide anions.…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Roy

Kern

Song

et al. 2017

The American Journal of Pathology

171

147

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Increasing evidence points to inflammation as one of the key players in diabetes-mediating adverse effects to the neuronal and vascular components of the retina. Sustained inflammation induces biochemical and molecular changes, ultimately contributing to retinal complications and vision loss in diabetic retinopathy. In this review, we describe changes involving metabolic abnormalities secondary to hyperglycemia, oxidative stress, and activation of transcription factors, together with neuroglial alterations in the diabetic retina. Changes in biochemical pathways and how they promote pathophysiologic developments involving proinflammatory cytokines, chemokines, and adhesion molecules are discussed. Inflammation-mediated leukostasis, retinal ischemia, and neovascularization and their contribution to pathological and clinical stages leading to vision loss in diabetic retinopathy (DR) are highlighted. In addition, potential treatment strategies involving fibrates, connexins, neuroprotectants, photobiomodulation, and anti-inflammatory agents against the development and progression of DR lesions are reviewed. The importance of appropriate animal models for testing novel strategies against DR lesions is discussed; in particular, a novel nonhuman primate model of DR and the suitability of rodent models are weighed. The purpose of this review is to highlight our current understanding of the pathogenesis of DR and to summarize recent advances using novel approaches or targets to investigate and inhibit the retinopathy. (Am J Pathol 2017, 187: 9e19; http://dx

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“…The mitochondrial respiratory machinery is regulated by both nuclear and mitochondrial genes. Their coordinated action is ensured by the PGC-1 family of coactivators, which, in turn, activate transcription factors such as NRF1 and NRF2 (36). NRF1 and NRF2 have overlapping but also distinct functions.…”

Section: Discussionmentioning

confidence: 99%

Activity Increase in Respiratory Chain Complexes by Rubella Virus with Marginal Induction of Oxidative Stress

Claus

Schönefeld

Hübner

et al. 2013

J Virol

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bMitochondria are important for the viral life cycle, mainly by providing the energy required for viral replication and assembly. A highly complex interaction with mitochondria is exerted by rubella virus (RV), which includes an increase in the mitochondrial membrane potential as a general marker for mitochondrial activity. We aimed in this study to provide a more comprehensive picture of the activity of mitochondrial respiratory chain complexes I to IV. Their activities were compared among three different cell lines. A strong and significant increase in the activity of mitochondrial respiratory enzyme succinate:ubiquinone oxidoreductase (complex II) and a moderate increase of ubiquinol:cytochrome c oxidoreductase (complex III) were detected in all cell lines. In contrast, the activity of mitochondrial respiratory enzyme cytochrome c oxidase (complex IV) was significantly decreased. The effects on mitochondrial functions appear to be RV specific, as they were absent in control infections with measles virus. Additionally, these alterations of the respiratory chain activity were not associated with an elevated transcription of oxidative stress proteins, and reactive oxygen species (ROS) were induced only marginally. Moreover, protein and/or mRNA levels of markers for mitochondrial biogenesis and structure were elevated, such as nuclear respiratory factors (NRFs) and mitofusin 2 (Mfn2). Together, these results establish a novel view on the regulation of mitochondrial functions by viruses. Mitochondria are required for the maintenance of cell function and integrity. Their most important role lies in energy production, but they are also at the intersection of regulatory pathways that coordinate metabolic processes (e.g., calcium homeostasis and cellular proliferation), cellular fate (apoptosis and necrosis), and antiviral defense (1, 2). Even a participation of mitochondria in the innate immune response was identified (2). There are a number of viruses that interfere with the important role of mitochondria in cellular antiviral response pathways, mainly with the regulation of apoptosis (1). Additionally, as the powerhouses of the cell, mitochondria provide most of the energy for viral replication and assembly. Up to 90% of the cellular ATP is produced in the inner mitochondrial membrane (IMM) by oxidative phosphorylation (OXPHOS), (3). OXPHOS comprises a series of redox reactions carried out by four multisubunit enzyme complexes (complexes I to IV) of the electron transport chain (ETC). Electrons are transferred in a stepwise manner through this series of electron carriers from NADH (and FADH 2 ) as reducing equivalents to the final acceptor molecular oxygen. A small percentage of electrons that are transported through the respiratory complexes leaks out, which results in generation of reactive oxygen species (ROS). The main ROS species is hydrogen peroxide, which is converted to water by enzymes such as catalase, peroxiredoxin, or glutathione peroxidase as components of the cellular antioxidant system. Respiratory c...

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Nucleus-encoded regulators of mitochondrial function: Integration of respiratory chain expression, nutrient sensing and metabolic stress

Cited by 138 publications

References 150 publications

Cardiac nuclear receptors: architects of mitochondrial structure and function

Cardiac nuclear receptors: architects of mitochondrial structure and function

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Activity Increase in Respiratory Chain Complexes by Rubella Virus with Marginal Induction of Oxidative Stress

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