Calcium-insensitive splice variants of mammalian E1 subunit of 2-oxoglutarate dehydrogenase complex with tissue-specific patterns of expression

2-Oxoglutarate dehydrogenase plays a central role in the regulation of intramitochondrial energy metabolism. We show that three Ca2+-insensitive splice variants are expressed to varying degrees in different tissues allowing potential important tuning to the metabolic needs of individual cell types.

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Studies on the regulation of the human E1 subunit of the 2-oxoglutarate dehydrogenase complex, including the identification of a novel calcium-binding site

Biochemical Journal ◽

10.1042/bj20131664 ◽

2014 ◽

Vol 459 (2) ◽

pp. 369-381 ◽

Cited By ~ 14

Author(s):

Craig T. Armstrong ◽

J. L. Ross Anderson ◽

Richard M. Denton

Keyword(s):

Energy Metabolism ◽

Binding Site ◽

Calcium Binding ◽

Adenine Nucleotides ◽

Calcium Binding Site ◽

Site Of Action ◽

Oxoglutarate Dehydrogenase ◽

Dehydrogenase Complex

The oxoglutarate dehydrogenase complex regulates energy metabolism through its sensitivity to adenine nucleotides, NADH and Ca2+. In the present study, we show definitively that the E1 subunit is the site of action for these regulators, and identify the Ca2+-binding site.

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Adult tissue-resident stem cells—fact or fiction?

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02142-x ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Deepa Bhartiya

Keyword(s):

Stem Cells ◽

Single Cell ◽

Adult Stem Cells ◽

Cell Types ◽

Specific Cell ◽

Tissue Specific ◽

Cardiac Tissues ◽

Adult Tissues ◽

Resident Stem Cells ◽

Abundant Cytoplasm

AbstractLife-long tissue homeostasis of adult tissues is supposedly maintained by the resident stem cells. These stem cells are quiescent in nature and rarely divide to self-renew and give rise to tissue-specific “progenitors” (lineage-restricted and tissue-committed) which divide rapidly and differentiate into tissue-specific cell types. However, it has proved difficult to isolate these quiescent stem cells as a physical entity. Recent single-cell RNAseq studies on several adult tissues including ovary, prostate, and cardiac tissues have not been able to detect stem cells. Thus, it has been postulated that adult cells dedifferentiate to stem-like state to ensure regeneration and can be defined as cells capable to replace lost cells through mitosis. This idea challenges basic paradigm of development biology regarding plasticity that a cell enters point of no return once it initiates differentiation. The underlying reason for this dilemma is that we are putting stem cells and somatic cells together while processing for various studies. Stem cells and adult mature cell types are distinct entities; stem cells are quiescent, small in size, and with minimal organelles whereas the mature cells are metabolically active and have multiple organelles lying in abundant cytoplasm. As a result, they do not pellet down together when centrifuged at 100–350g. At this speed, mature cells get collected but stem cells remain buoyant and can be pelleted by centrifuging at 1000g. Thus, inability to detect stem cells in recently published single-cell RNAseq studies is because the stem cells were unknowingly discarded while processing and were never subjected to RNAseq. This needs to be kept in mind before proposing to redefine adult stem cells.

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Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex

Biochemical Journal ◽

10.1042/bj3290191 ◽

1998 ◽

Vol 329 (1) ◽

pp. 191-196 ◽

Cited By ~ 345

Author(s):

Melissa M. BOWKER-KINLEY ◽

I. Wilhelmina DAVIS ◽

Pengfei WU ◽

A. Robert HARRIS ◽

M. Kirill POPOV

Keyword(s):

Tissue Distribution ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Pyruvate Dehydrogenase Kinase ◽

Synthetic Analogue ◽

Complex Activity ◽

Acetyl Coa ◽

Tissue Specific ◽

Specific Regulation ◽

Dehydrogenase Complex

Tissue distribution and kinetic parameters for the four isoenzymes of pyruvate dehydrogenase kinase (PDK1, PDK2, PDK3 and PDK4) identified thus far in mammals were analysed. It appeared that expression of these isoenzymes occurs in a tissue-specific manner. The mRNA for isoenzyme PDK1 was found almost exclusively in rat heart. The mRNA for PDK3 was most abundantly expressed in rat testis. The message for PDK2 was present in all tissues tested but the level was low in spleen and lung. The mRNA for PDK4 was predominantly expressed in skeletal muscle and heart. The specific activities of the isoenzymes varied 25-fold, from 50 nmol/min per mg for PDK2 to 1250 nmol/min per mg for PDK3. Apparent Ki values of the isoenzymes for the synthetic analogue of pyruvate, dichloroacetate, varied 40-fold, from 0.2 mM for PDK2 to 8 mM for PDK3. The isoenzymes were also different with respect to their ability to respond to NADH and NADH plus acetyl-CoA. NADH alone stimulated the activities of PDK1 and PDK2 by 20 and 30% respectively. NADH plus acetyl-CoA activated these isoenzymes nearly 200 and 300%. Under comparable conditions, isoenzyme PDK3 was almost completely unresponsive to NADH, and NADH plus acetyl-CoA caused inhibition rather than activation. Isoenzyme PDK4 was activated almost 2-fold by NADH, but NADH plus acetyl-CoA did not activate above the level seen with NADH alone. These results provide the first evidence that the unique tissue distribution and kinetic characteristics of the isoenzymes of PDK are among the major factors responsible for tissue-specific regulation of the pyruvate dehydrogenase complex activity.

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Mitochondrial DNA Heteroplasmy as an Informational Reservoir Dynamically Linked to Metabolic and Immunological Processes Associated with COVID-19 Neurological Disorders

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01117-z ◽

2021 ◽

Author(s):

George B. Stefano ◽

Richard M. Kream

Keyword(s):

Mitochondrial Dna ◽

Mitochondrial Function ◽

Neurological Disorders ◽

Nuclear Dna ◽

Mitochondrial Dynamics ◽

Cell Types ◽

Tissue Specific ◽

Copy Numbers ◽

The Central Nervous System ◽

Mitochondrial Dna Heteroplasmy

AbstractMitochondrial DNA (mtDNA) heteroplasmy is the dynamically determined co-expression of wild type (WT) inherited polymorphisms and collective time-dependent somatic mutations within individual mtDNA genomes. The temporal expression and distribution of cell-specific and tissue-specific mtDNA heteroplasmy in healthy individuals may be functionally associated with intracellular mitochondrial signaling pathways and nuclear DNA gene expression. The maintenance of endogenously regulated tissue-specific copy numbers of heteroplasmic mtDNA may represent a sensitive biomarker of homeostasis of mitochondrial dynamics, metabolic integrity, and immune competence. Myeloid cells, monocytes, macrophages, and antigen-presenting dendritic cells undergo programmed changes in mitochondrial metabolism according to innate and adaptive immunological processes. In the central nervous system (CNS), the polarization of activated microglial cells is dependent on strategically programmed changes in mitochondrial function. Therefore, variations in heteroplasmic mtDNA copy numbers may have functional consequences in metabolically competent mitochondria in innate and adaptive immune processes involving the CNS. Recently, altered mitochondrial function has been demonstrated in the progression of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Accordingly, our review is organized to present convergent lines of empirical evidence that potentially link expression of mtDNA heteroplasmy by functionally interactive CNS cell types to the extent and severity of acute and chronic post-COVID-19 neurological disorders.

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P4-154: Succinyl phosphonate, a protector of the 2-oxoglutarate dehydrogenase complex, corrects behavioral impairments in rats exposed to hypoxia or ethanol

Alzheimer s & Dementia ◽

10.1016/j.jalz.2009.04.721 ◽

2009 ◽

Vol 5 (4S_Part_16) ◽

pp. P476-P477 ◽

Cited By ~ 1

Author(s):

Victoria I. Bunik ◽

Maxim Lovat ◽

Alexandra Groznaya ◽

Anastasia Graf ◽

Tatiana Dunaeva ◽

...

Keyword(s):

Oxoglutarate Dehydrogenase ◽

Behavioral Impairments ◽

Dehydrogenase Complex

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Expression of the genes for the ferritin H and L subunits in rat liver and heart. Evidence for tissue-specific regulations at pre- and post-translational levels

Biochemical Journal ◽

10.1042/bj2750813 ◽

1991 ◽

Vol 275 (3) ◽

pp. 813-816 ◽

Cited By ~ 38

Author(s):

G Cairo ◽

E Rappocciolo ◽

L Tacchini ◽

L Schiaffonati

Keyword(s):

Translational Regulation ◽

Specific Pattern ◽

Regulatory Mechanisms ◽

Mrna Accumulation ◽

Tissue Specific ◽

Protein Levels ◽

Ferritin Gene ◽

Ferritin H ◽

Translational Mechanisms ◽

Different Tissues

The proportion of ferritin light-chain and heavy-chain subunits (L and H) present in the ferritin multimeric shell varies between different tissues. To identify the regulatory mechanisms responsible for the greater amount of L in liver than in heart isoferritins, we analysed ferritin-gene expression at the RNA and protein levels in these two tissues of the rat. In the heart the ratio between the amount of L and H, at the level both of synthesis and accumulation, is about 1 and is the same as the ratio between their respective mRNAs. In contrast, in the liver, the ratio between the L- and H-mRNAs is approx. 2 and cannot entirely explain the large predominance of L in isoferritins in this tissue. Since in the liver the L-mRNA is neither preferentially associated with polyribosomes nor translated more efficiently than its H- counterpart, it seems that the liver-specific isoferritin profile is determined by a combination of pre- and post-translational mechanisms, whereas in heart the post-translational regulation does not seem to be relevant and the tissue-specific pattern is determined at the level of mRNA accumulation.

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Chimeric Maternal Cells with Tissue-Specific Antigen Expression and Morphology Are Common in Infant Tissues

Pediatric and Developmental Pathology ◽

10.2350/08-07-0499.1 ◽

2009 ◽

Vol 12 (5) ◽

pp. 337-346 ◽

Cited By ~ 26

Author(s):

Anne M. Stevens ◽

Heidi M. Hermes ◽

Meghan M. Kiefer ◽

Joe C. Rutledge ◽

J. Lee Nelson

Keyword(s):

Islet Cells ◽

Tissue Injury ◽

Specific Antigen ◽

Antigen Expression ◽

Cell Types ◽

Target Cells ◽

Specific Cell ◽

Tissue Specific ◽

Renal Tubular Cells ◽

Parenchymal Cells

Maternal microchimerism (MMc) has been purported to play a role in the pathogenesis of autoimmunity, but how a small number of foreign cells could contribute to chronic, systemic inflammation has not been explained. Reports of peripheral blood cells differentiating into tissue-specific cell types may shed light on the problem in that chimeric maternal cells could act as target cells within tissues. We investigated MMc in tissues from 7 male infants. Female cells, presumed maternal, were characterized by simultaneous immunohistochemistry and fluorescence in situ hybridization for X- and Y-chromosomes. Maternal cells constituted 0.017% to 1.9% of parenchymal cells and were found in all infants in liver, pancreas, lung, kidney, bladder, skin, and spleen. Maternal cells were differentiated: maternal hepatocytes in liver, renal tubular cells in kidney, and β-islet cells in pancreas. Maternal cells were not found in areas of tissue injury or inflammatory infiltrate. Maternal hematopoietic cells were found only in hearts from patients with neonatal lupus. Thus, differentiated maternal cells are present in multiple tissue types and occur independently of inflammation or tissue injury. Loss of tolerance to maternal parenchymal cells could lead to organ-specific “auto” inflammatory disease and elimination of maternal cells in areas of inflammation.

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Stable transfer and restricted expression of a cloned class I gene encoding a secreted transplantation-like antigen

Molecular and Cellular Biology ◽

10.1128/mcb.5.6.1295-1300.1985 ◽

1985 ◽

Vol 5 (6) ◽

pp. 1295-1300

Author(s):

Y Barra ◽

K Tanaka ◽

K J Isselbacher ◽

G Khoury ◽

G Jay

Keyword(s):

Molecular Mechanisms ◽

Cell Types ◽

Class I ◽

Regulatory Sequences ◽

Transcriptional Enhancer ◽

Gene Encoding ◽

Specific Expression ◽

Tissue Specific ◽

Functional Studies ◽

I Gene

The identification of a unique major histocompatibility complex class I gene, designated Q10, which encodes a secreted rather than a cell surface antigen has led to questions regarding its potential role in regulating immunological functions. Since the Q10 gene is specifically activated only in the liver, we sought to define the molecular mechanisms which control its expression in a tissue-specific fashion. Results obtained by transfection of the cloned Q10 gene, either in the absence or presence of a heterologous transcriptional enhancer, into a variety of cell types of different tissue derivations are consistent with the Q10 gene being regulated at two levels. The first is by a cis-dependent mechanism which appears to involve site-specific DNA methylation. The second is by a trans-acting mechanism which would include the possibility of an enhancer binding factor. The ability to efficiently express the Q10 gene in certain transfected cell lines offers an opportunity to obtain this secreted class I antigen in quantities sufficient for functional studies; this should also make it possible to define regulatory sequences which may be responsible for the tissue-specific expression of Q10.

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Homeotic response elements are tightly linked to tissue-specific elements in a transcriptional enhancer of the teashirt gene

Development ◽

10.1242/dev.121.9.2799 ◽

1995 ◽

Vol 121 (9) ◽

pp. 2799-2812 ◽

Cited By ~ 4

Author(s):

A. McCormick ◽

N. Core ◽

S. Kerridge ◽

M.P. Scott

Keyword(s):

Transcriptional Activation ◽

Target Genes ◽

Hox Genes ◽

Zinc Finger Protein ◽

Cell Types ◽

Transcriptional Enhancer ◽

Hox Proteins ◽

Tissue Specific ◽

Conserved Sequences

Along the anterior-posterior axis of animal embryos, the choice of cell fates, and the organization of morphogenesis, is regulated by transcription factors encoded by clustered homeotic or ‘Hox’ genes. Hox genes function in both epidermis and internal tissues by regulating the transcription of target genes in a position- and tissue-specific manner. Hox proteins can have distinct targets in different tissues; the mechanisms underlying tissue and homeotic protein specificity are unknown. Light may be shed by studying the organization of target gene enhancers. In flies, one of the target genes is teashirt (tsh), which encodes a zinc finger protein. tsh itself is a homeotic gene that controls trunk versus head development. We identified a tsh gene enhancer that is differentially activated by Hox proteins in epidermis and mesoderm. Sites where Antennapedia (Antp) and Ultrabithorax (Ubx) proteins bind in vitro were mapped within evolutionarily conserved sequences. Although Antp and Ubx bind to identical sites in vitro, Antp activates the tsh enhancer only in epidermis while Ubx activates the tsh enhancer in both epidermis and in somatic mesoderm. We show that the DNA elements driving tissue-specific transcriptional activation by Antp and Ubx are separable. Next to the homeotic protein-binding sites are extensive conserved sequences likely to control tissue activation by different homeodomain proteins. We propose that local interactions between homeotic proteins and other factors effect activation of targets in proper cell types.

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