Nuclear Respiratory Factor 1 Regulates All Ten Nuclear-encoded Subunits of Cytochrome c Oxidase in Neurons

Dhar, S.; Ongwijitwat, Sakkapol; Wong‐Riley, Margaret T.T.

doi:10.1074/jbc.m707587200

Cited by 146 publications

(205 citation statements)

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“…Nrf1 occupies an upstream position in the hierarchy of transcription factors coordinating mitochondrial biogenesis and function. Nrf1, in collaboration with PGC-1α, controls oxidative phosphorylation through the expression of many key nuclear-encoded mitochondrial genes, including all cytochrome c oxidase nuclearencoded subunit genes (37,38). Interestingly, several PD-related genes such as PARK2 (Parkin), PARK6 (Pink1), PARK7 (DJ-1), and PAELR (GPR37) have been identified as NRF1 targets (39).…”

Section: Discussionmentioning

confidence: 99%

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Doucet-Beaupré

Gilbert

Profes

et al. 2016

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

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The LIM-homeodomain transcription factors Lmx1a and Lmx1b play critical roles during the development of midbrain dopaminergic progenitors, but their functions in the adult brain remain poorly understood. We show here that sustained expression of Lmx1a and Lmx1b is required for the survival of adult midbrain dopaminergic neurons. Strikingly, inactivation of Lmx1a and Lmx1b recreates cellular features observed in Parkinson's disease. We found that Lmx1a/b control the expression of key genes involved in mitochondrial functions, and their ablation results in impaired respiratory chain activity, increased oxidative stress, and mitochondrial DNA damage. Lmx1a/b deficiency caused axonal pathology characterized by α-synuclein + inclusions, followed by a progressive loss of dopaminergic neurons. These results reveal the key role of these transcription factors beyond the early developmental stages and provide mechanistic links between mitochondrial dysfunctions, α-synuclein aggregation, and the survival of dopaminergic neurons. M idbrain dopaminergic (mDA) neurons control key functions in the mammalian brain, including voluntary movement, associative learning, and motivated behaviors. Dysfunctions of the dopaminergic (DA) system underlie a wide variety of neurological and psychiatric disorders. The progressive and rather selective degeneration of mDA neurons is one of the principal pathological features of Parkinson's disease (PD) (1). In PD, neuronal loss is accompanied by the appearance of α-synucleinenriched intraneuronal inclusions called "Lewy bodies" and "Lewy neurites." The etiologies of PD remain unsolved, but mitochondrial dysfunction emerges as a central mechanism in inherited, sporadic, and toxin-induced PD (2).Specification of the subtype identities of mDA neurons begins during embryonic development. The combinatory activation of transcription factors (TFs) and their target genes allows the progenitors to mature progressively and terminally differentiate into postmitotic neuron subtypes. Tremendous efforts have been made to describe the complex spatiotemporal expression of TFs during mDA neuronal development (see refs. 3 and 4 for reviews). After mDA neuron maturation, a large number of developmentally expressed TFs remain active throughout adulthood. Our knowledge of the functional roles of these TFs in mature neurons remains rudimentary. Accumulating evidence shows that transcription factors including the nuclear receptor related 1 protein (Nurr1), En1, Pitx3, Otx2, and Foxa2, which are recognized for their role in the early development of mDA neurons, are also required for the maintenance of phenotypic neuronal identity in the adult (5).The LIM homeodomain genes Lmx1a/b are early determinants of the fate of mDA progenitors (6), and their actions are essential at each step of DA neuronal generation (7,8). The murine Lmx1a and Lmx1b proteins are closely related and share an overall amino acid identity of 64%, with 100% identity in their homeodomain and 67% and 83% identity in each LIM domain (9). These neuron...

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Section: Discussionmentioning

confidence: 99%

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Doucet-Beaupré

Gilbert

Profes

et al. 2016

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

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“…Real time quantitative PCRs were carried out in a Cepheid Smart Cycler detection system (Cepheid, Sunnyvale, CA). SyBr Green (Biowhittaker Molecular Application, Rockland, ME) and EX Taq real time quantitative PCR hot start polymerase (Takara Mirus Bio, Madison, WI) were used following the manufacturer's protocols and as described previously (11).…”

Section: Methodsmentioning

confidence: 99%

Chromosome Conformation Capture of All 13 Genomic Loci in the Transcriptional Regulation of the Multisubunit Bigenomic Cytochrome c Oxidase in Neurons

Dhar

Ongwijitwat

Wong‐Riley

2009

Journal of Biological Chemistry

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Cytochrome c oxidase (COX) is the terminal enzyme of the electron transport chain composed of 13 subunits; three are mitochondria-encoded, and 10 are nucleus-inscribed on nine different chromosomes within the mammalian genome. The transcriptional regulation of such a multisubunit, multichromosomal, and bigenomic enzyme is mechanistically challenging. Transcription factories have been proposed as one mechanism by which genes from different genomic loci congregate to transcribe functionally related genes, and chromosome conformation capture (3C) is a means by which such interactions can be revealed. Thus far, however, only loci from the same chromosome or at most two chromosomes have been co-localized by 3C. The present study used 3C to test our hypothesis that not only the 10 genomic loci from nine chromosomes encoding the 10 nuclear subunits of COX, but also genes from three chromosomes encoding mitochondrial transcription factors A and B (Tfam, Tfb1m, and Tfb2m) critical for the transcription of the three mitochondria-encoded COX subunit genes all occupy common intranuclear sites in the murine neuronal nuclei. The pairing of various COX subunit genes and Tf genes indicates that interactions are present among all of them. On the other hand, genes for a non-mitochondrial protein (calreticulin) as well as a mitochondrial enzyme (citrate synthase) did not interact with COX genes. Furthermore, interactions between COX subunit and Tf genes were up-regulated by depolarizing stimulation and down-regulated by impulse blockade in primary neurons. Thus, a viable mechanism is in place for a synchronized, coordinated transcriptional regulation of this multisubunit, bigenomic COX enzyme in neurons.Cytochrome c oxidase (COX) 2 or complex IV of the mitochondrial electron transport chain is made up of three subunits encoded in the mitochondrial genome and 10 nucleus-encoded subunits located on nine different chromosomes (1-3). The 10 nucleus-encoded COX subunits are 4, 5a, 5b, 6a, 6b, 6c, 7a, 7b, 7c, and 8a. Subunits 4, 6a, 6b, 7a, and 8a each has a ubiquitous isoform and a tissue-specific isoform. Transcription of all ubiquitously expressed subunits in neurons are coordinately regulated according to the cell's ATP requirement (4). Transcriptional regulators of COX in rats, mice, and humans include NRF-1 and NRF-2 (nuclear respiratory factors 1 and 2) (5-8).In particular, both NRF-1 and NRF-2 activate the transcription of all 10 nucleus-encoded COX subunits and modulate the level of transcription in response to changing cellular energy demands in neurons (9 -14). Additionally, NRF-1 and NRF-2 indirectly activate the three mitochondria-encoded COX subunit genes by regulating Tfam, Tfb1m, and Tfb2m (mitochondrial transcription factors A, B1, and B2) critical for mitochondrial DNA transcription and replication (15-18). Transcriptional coactivators, such as PGC-1␣ (peroxisome proliferator-activated receptor ␥-coactivator 1␣) (19,20), also play an important role in stimulating COX transcription in the presence of upstream signals i...

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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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Nuclear Respiratory Factor 1 Regulates All Ten Nuclear-encoded Subunits of Cytochrome c Oxidase in Neurons

Cited by 146 publications

References 55 publications

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Lmx1a and Lmx1b regulate mitochondrial functions and survival of adult midbrain dopaminergic neurons

Chromosome Conformation Capture of All 13 Genomic Loci in the Transcriptional Regulation of the Multisubunit Bigenomic Cytochrome c Oxidase in Neurons

Cardiac nuclear receptors: architects of mitochondrial structure and function

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