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  1. Artikel ; Online: Mitochondrial functional resilience after TFAM ablation in the adult heart.

    Ghazal, Nasab / Peoples, Jessica N / Mohiuddin, Tahmina A / Kwong, Jennifer Q

    American journal of physiology. Cell physiology

    2021  Band 320, Heft 6, Seite(n) C929–C942

    Abstract: The nuclear genome-encoded mitochondrial DNA (mtDNA) transcription factor A (TFAM) is indispensable for mitochondrial energy production in the developing and postnatal heart; a similar role for TFAM is inferred in adult heart. Here, we provide evidence ... ...

    Abstract The nuclear genome-encoded mitochondrial DNA (mtDNA) transcription factor A (TFAM) is indispensable for mitochondrial energy production in the developing and postnatal heart; a similar role for TFAM is inferred in adult heart. Here, we provide evidence that challenges this long-standing paradigm. Unexpectedly, conditional
    Mesh-Begriff(e) Animals ; DNA Replication/genetics ; DNA, Mitochondrial/genetics ; DNA-Binding Proteins/genetics ; Down-Regulation/genetics ; Electron Transport/genetics ; Female ; Gene Expression Regulation/genetics ; Heart/physiology ; High Mobility Group Proteins/genetics ; Male ; Mice ; Mitochondria/genetics ; Mitochondrial Proteins/genetics ; Myocytes, Cardiac/metabolism ; Transcription Factors/genetics ; Transcription, Genetic/genetics
    Chemische Substanzen DNA, Mitochondrial ; DNA-Binding Proteins ; High Mobility Group Proteins ; Mitochondrial Proteins ; Tfam protein, mouse ; Transcription Factors
    Sprache Englisch
    Erscheinungsdatum 2021-03-24
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00508.2020
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel: Mitochondrial citrate carrier SLC25A1 is a dosage-dependent regulator of metabolic reprogramming and morphogenesis in the developing heart.

    Ohanele, Chiemela / Peoples, Jessica N / Karlstaedt, Anja / Geiger, Joshua T / Gayle, Ashley D / Ghazal, Nasab / Sohani, Fateemaa / Brown, Milton E / Davis, Michael E / Porter, George A / Faundez, Victor / Kwong, Jennifer Q

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The developing mammalian heart undergoes an important metabolic shift from glycolysis toward mitochondrial oxidation, such that oxidative phosphorylation defects may present with cardiac abnormalities. Here, we describe a new mechanistic link between ... ...

    Abstract The developing mammalian heart undergoes an important metabolic shift from glycolysis toward mitochondrial oxidation, such that oxidative phosphorylation defects may present with cardiac abnormalities. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mice with systemic loss of the mitochondrial citrate carrier SLC25A1. Slc25a1 null embryos displayed impaired growth, cardiac malformations, and aberrant mitochondrial function. Importantly, Slc25a1 heterozygous embryos, which are overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 haploinsuffiency and dose-dependent effects. Supporting clinical relevance, we found a near-significant association between ultrarare human pathogenic SLC25A1 variants and pediatric congenital heart disease. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of gene expression to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of ventricular morphogenesis and cardiac metabolic maturation and suggests a role in congenital heart disease.
    Sprache Englisch
    Erscheinungsdatum 2024-05-13
    Erscheinungsland United States
    Dokumenttyp Preprint
    DOI 10.1101/2023.05.22.541833
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Intact calcium signaling in adrenergic-deficient embryonic mouse hearts.

    Peoples, Jessica N / Taylor, David G / Katchman, Alexander N / Ebert, Steven N

    Biochemical and biophysical research communications

    2018  Band 495, Heft 4, Seite(n) 2547–2552

    Abstract: Mouse embryos that lack the ability to produce the adrenergic hormones, norepinephrine (NE) and epinephrine (EPI), due to disruption of the dopamine beta-hydroxylase ( ... ...

    Abstract Mouse embryos that lack the ability to produce the adrenergic hormones, norepinephrine (NE) and epinephrine (EPI), due to disruption of the dopamine beta-hydroxylase (Dbh
    Mesh-Begriff(e) Adrenergic Agents/metabolism ; Animals ; Calcium/metabolism ; Calcium Signaling/physiology ; Epinephrine/metabolism ; Heart/embryology ; Mice ; Mice, Knockout ; Myocardium/metabolism ; Norepinephrine/metabolism
    Chemische Substanzen Adrenergic Agents ; Calcium (SY7Q814VUP) ; Norepinephrine (X4W3ENH1CV) ; Epinephrine (YKH834O4BH)
    Sprache Englisch
    Erscheinungsdatum 2018--22
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 205723-2
    ISSN 1090-2104 ; 0006-291X ; 0006-291X
    ISSN (online) 1090-2104 ; 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2017.12.155
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  4. Artikel ; Online: Loss of the mitochondrial phosphate carrier SLC25A3 induces remodeling of the cardiac mitochondrial protein acylome.

    Peoples, Jessica N / Ghazal, Nasab / Duong, Duc M / Hardin, Katherine R / Manning, Janet R / Seyfried, Nicholas T / Faundez, Victor / Kwong, Jennifer Q

    American journal of physiology. Cell physiology

    2021  Band 321, Heft 3, Seite(n) C519–C534

    Abstract: Mitochondria are recognized as signaling organelles, because under stress, mitochondria can trigger various signaling pathways to coordinate the cell's response. The specific pathway(s) engaged by mitochondria in response to mitochondrial energy defects ... ...

    Abstract Mitochondria are recognized as signaling organelles, because under stress, mitochondria can trigger various signaling pathways to coordinate the cell's response. The specific pathway(s) engaged by mitochondria in response to mitochondrial energy defects in vivo and in high-energy tissues like the heart are not fully understood. Here, we investigated cardiac pathways activated in response to mitochondrial energy dysfunction by studying mice with cardiomyocyte-specific loss of the mitochondrial phosphate carrier (SLC25A3), an established model that develops cardiomyopathy as a result of defective mitochondrial ATP synthesis. Mitochondrial energy dysfunction induced a striking pattern of acylome remodeling, with significantly increased posttranslational acetylation and malonylation. Mass spectrometry-based proteomics further revealed that energy dysfunction-induced remodeling of the acetylome and malonylome preferentially impacts mitochondrial proteins. Acetylation and malonylation modified a highly interconnected interactome of mitochondrial proteins, and both modifications were present on the enzyme isocitrate dehydrogenase 2 (IDH2). Intriguingly, IDH2 activity was enhanced in SLC25A3-deleted mitochondria, and further study of IDH2 sites targeted by both acetylation and malonylation revealed that these modifications can have site-specific and distinct functional effects. Finally, we uncovered a novel cross talk between the two modifications, whereby mitochondrial energy dysfunction-induced acetylation of sirtuin 5 (SIRT5), inhibited its function. Because SIRT5 is a mitochondrial deacylase with demalonylase activity, this finding suggests that acetylation can modulate the malonylome. Together, our results position acylations as an arm of the mitochondrial response to energy dysfunction and suggest a mechanism by which focal disruption to the energy production machinery can have an expanded impact on global mitochondrial function.
    Mesh-Begriff(e) Acetylation ; Animals ; Biological Transport ; Cardiomyopathies/genetics ; Cardiomyopathies/metabolism ; Cardiomyopathies/pathology ; Cation Transport Proteins/deficiency ; Cation Transport Proteins/genetics ; Energy Metabolism ; Female ; Gene Regulatory Networks ; Isocitrate Dehydrogenase/genetics ; Isocitrate Dehydrogenase/metabolism ; Male ; Malonates/metabolism ; Mice ; Mice, Knockout ; Mitochondria, Heart/genetics ; Mitochondria, Heart/metabolism ; Mitochondria, Heart/pathology ; Mitochondrial Proteins/deficiency ; Mitochondrial Proteins/genetics ; Models, Molecular ; Myocardium/metabolism ; Myocardium/pathology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/pathology ; Phosphate Transport Proteins/deficiency ; Phosphate Transport Proteins/genetics ; Phosphates ; Protein Conformation ; Protein Interaction Mapping ; Protein Processing, Post-Translational ; Signal Transduction ; Sirtuins/genetics ; Sirtuins/metabolism ; Solute Carrier Proteins/deficiency ; Solute Carrier Proteins/genetics
    Chemische Substanzen Cation Transport Proteins ; Malonates ; Mitochondrial Proteins ; Phosphate Transport Proteins ; Phosphates ; SIRT5 protein, mouse ; Slc25a3 protein, mouse ; Solute Carrier Proteins ; malonic acid (9KX7ZMG0MK) ; Isocitrate Dehydrogenase (EC 1.1.1.41) ; isocitrate dehydrogenase 2, mouse (EC 1.1.1.41) ; Sirtuins (EC 3.5.1.-)
    Sprache Englisch
    Erscheinungsdatum 2021-07-28
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00156.2021
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  5. Artikel ; Online: Mitochondrial dysfunction and oxidative stress in heart disease.

    Peoples, Jessica N / Saraf, Anita / Ghazal, Nasab / Pham, Tyler T / Kwong, Jennifer Q

    Experimental & molecular medicine

    2019  Band 51, Heft 12, Seite(n) 1–13

    Abstract: Beyond their role as a cellular powerhouse, mitochondria are emerging as integral players in molecular signaling and cell fate determination through reactive oxygen species (ROS). While ROS production has historically been portrayed as an unregulated ... ...

    Abstract Beyond their role as a cellular powerhouse, mitochondria are emerging as integral players in molecular signaling and cell fate determination through reactive oxygen species (ROS). While ROS production has historically been portrayed as an unregulated process driving oxidative stress and disease pathology, contemporary studies reveal that ROS also facilitate normal physiology. Mitochondria are especially abundant in cardiac tissue; hence, mitochondrial dysregulation and ROS production are thought to contribute significantly to cardiac pathology. Moreover, there is growing appreciation that medical therapies designed to mediate mitochondrial ROS production can be important strategies to ameliorate cardiac disease. In this review, we highlight evidence from animal models that illustrates the strong connections between mitochondrial ROS and cardiac disease, discuss advancements in the development of mitochondria-targeted antioxidant therapies, and identify challenges faced in bringing such therapies into the clinic.
    Mesh-Begriff(e) Animals ; Cardiomyopathies/metabolism ; Heart Diseases/metabolism ; Humans ; Mitochondria/metabolism ; Mitochondrial Diseases/metabolism ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction
    Chemische Substanzen Reactive Oxygen Species
    Sprache Englisch
    Erscheinungsdatum 2019-12-19
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1328915-9
    ISSN 2092-6413 ; 1226-3613 ; 0378-8512
    ISSN (online) 2092-6413
    ISSN 1226-3613 ; 0378-8512
    DOI 10.1038/s12276-019-0355-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  6. Artikel: Intact calcium signaling in adrenergic-deficient embryonic mouse hearts

    Peoples, Jessica N / Taylor, David G / Katchman, Alexander N / Ebert, Steven N

    Biochemical and biophysical research communications. 2018 Jan. 22, v. 495, no. 4

    2018  

    Abstract: Mouse embryos that lack the ability to produce the adrenergic hormones, norepinephrine (NE) and epinephrine (EPI), due to disruption of the dopamine beta-hydroxylase (Dbh−/-) gene inevitably perish from heart failure during mid-gestation. Since ... ...

    Abstract Mouse embryos that lack the ability to produce the adrenergic hormones, norepinephrine (NE) and epinephrine (EPI), due to disruption of the dopamine beta-hydroxylase (Dbh−/-) gene inevitably perish from heart failure during mid-gestation. Since adrenergic stimulation is well-known to enhance calcium signaling in developing as well as adult myocardium, and impairments in calcium signaling are typically associated with heart failure, we hypothesized that adrenergic-deficient embryonic hearts would display deficiencies in cardiac calcium signaling relative to adrenergic-competent controls at a developmental stage immediately preceding the onset of heart failure, which first appears beginning or shortly after mouse embryonic day 10.5 (E10.5). To test this hypothesis, we used ratiometric fluorescent calcium imaging techniques to measure cytosolic calcium transients, [Ca2+]i in isolated E10.5 mouse hearts. Our results show that spontaneous [Ca2+]i oscillations were intact and robustly responded to a variety of stimuli including extracellular calcium (5 mM), caffeine (5 mM), and NE (100 nM) in a manner that was indistinguishable from controls. Further, we show similar patterns of distribution (via immunofluorescent histochemical staining) and activity (via patch-clamp recording techniques) for the major voltage-gated plasma membrane calcium channel responsible for the L-type calcium current, ICa,L, in adrenergic-deficient and control embryonic cardiac cells. These results demonstrate that despite the absence of vital adrenergic hormones that consistently leads to embryonic lethality in vivo, intracellular and extracellular calcium signaling remain essentially intact and functional in embryonic mouse hearts through E10.5. These findings suggest that adrenergic stimulation is not required for the development of intracellular calcium oscillations or extracellular calcium signaling through ICa,L and that aberrant calcium signaling does not likely contribute to the onset of heart failure in this model.
    Schlagwörter adults ; caffeine ; calcium ; calcium channels ; dopamine beta-monooxygenase ; embryonic mortality ; epinephrine ; fluorescence ; genes ; heart failure ; mice ; models ; myocardium ; norepinephrine ; plasma membrane ; pregnancy ; research
    Sprache Englisch
    Erscheinungsverlauf 2018-0122
    Umfang p. 2547-2552.
    Erscheinungsort Elsevier Inc.
    Dokumenttyp Artikel
    Anmerkung NAL-AP-2-clean
    ZDB-ID 205723-2
    ISSN 0006-291X ; 0006-291X
    ISSN (online) 0006-291X
    ISSN 0006-291X
    DOI 10.1016/j.bbrc.2017.12.155
    Datenquelle NAL Katalog (AGRICOLA)

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  7. Artikel ; Online: Metabolomics reveals critical adrenergic regulatory checkpoints in glycolysis and pentose-phosphate pathways in embryonic heart.

    Peoples, Jessica N R / Maxmillian, Timmi / Le, Quynh / Nadtochiy, Sergiy M / Brookes, Paul S / Porter, George A / Davidson, Victor L / Ebert, Steven N

    The Journal of biological chemistry

    2018  Band 293, Heft 18, Seite(n) 6925–6941

    Abstract: Cardiac energy demands during early embryonic periods are sufficiently met through glycolysis, but as development proceeds, the oxidative phosphorylation in mitochondria becomes increasingly vital. Adrenergic hormones are known to stimulate metabolism in ...

    Abstract Cardiac energy demands during early embryonic periods are sufficiently met through glycolysis, but as development proceeds, the oxidative phosphorylation in mitochondria becomes increasingly vital. Adrenergic hormones are known to stimulate metabolism in adult mammals and are essential for embryonic development, but relatively little is known about their effects on metabolism in the embryonic heart. Here, we show that embryos lacking adrenergic stimulation have ∼10-fold less cardiac ATP compared with littermate controls. Despite this deficit in steady-state ATP, neither the rates of ATP formation nor degradation was affected in adrenergic hormone-deficient hearts, suggesting that ATP synthesis and hydrolysis mechanisms were fully operational. We thus hypothesized that adrenergic hormones stimulate metabolism of glucose to provide chemical substrates for oxidation in mitochondria. To test this hypothesis, we employed a metabolomics-based approach using LC/MS. Our results showed glucose 1-phosphate and glucose 6-phosphate concentrations were not significantly altered, but several downstream metabolites in both glycolytic and pentose-phosphate pathways were significantly lower compared with controls. Furthermore, we identified glyceraldehyde-3-phosphate dehydrogenase and glucose-6-phosphate dehydrogenase as key enzymes in those respective metabolic pathways whose activity was significantly (
    Mesh-Begriff(e) Adenosine Triphosphate/biosynthesis ; Adenosine Triphosphate/metabolism ; Animals ; Epinephrine/metabolism ; Female ; Glucose/metabolism ; Glucose-6-Phosphate/metabolism ; Glucosephosphate Dehydrogenase/metabolism ; Glucosephosphates/metabolism ; Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)/metabolism ; Glycolysis ; Heart/embryology ; Hydrolysis ; Ketone Oxidoreductases/metabolism ; Male ; Metabolomics ; Mice, Inbred C57BL ; Mitochondria, Heart/metabolism ; Myocardium/metabolism ; Norepinephrine/metabolism ; Pentose Phosphate Pathway ; Phosphorylation ; Pregnancy
    Chemische Substanzen Glucosephosphates ; Glucose-6-Phosphate (56-73-5) ; Adenosine Triphosphate (8L70Q75FXE) ; glucose-1-phosphate (CIX3U01VAU) ; Glucosephosphate Dehydrogenase (EC 1.1.1.49) ; Ketone Oxidoreductases (EC 1.2.-) ; pyruvate dehydrogenase (NADP+) (EC 1.2.1.51) ; Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) (EC 1.2.1.9) ; Glucose (IY9XDZ35W2) ; Norepinephrine (X4W3ENH1CV) ; Epinephrine (YKH834O4BH)
    Sprache Englisch
    Erscheinungsdatum 2018-03-14
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.RA118.002566
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  8. Artikel ; Online: Impaired cardiac energy metabolism in embryos lacking adrenergic stimulation.

    Baker, Candice N / Gidus, Sarah A / Price, George F / Peoples, Jessica N R / Ebert, Steven N

    American journal of physiology. Endocrinology and metabolism

    2014  Band 308, Heft 5, Seite(n) E402–13

    Abstract: As development proceeds from the embryonic to fetal stages, cardiac energy demands increase substantially, and oxidative phosphorylation of ADP to ATP in mitochondria becomes vital. Relatively little, however, is known about the signaling mechanisms ... ...

    Abstract As development proceeds from the embryonic to fetal stages, cardiac energy demands increase substantially, and oxidative phosphorylation of ADP to ATP in mitochondria becomes vital. Relatively little, however, is known about the signaling mechanisms regulating the transition from anaerobic to aerobic metabolism that occurs during the embryonic period. The main objective of this study was to test the hypothesis that adrenergic hormones provide critical stimulation of energy metabolism during embryonic/fetal development. We examined ATP and ADP concentrations in mouse embryos lacking adrenergic hormones due to targeted disruption of the essential dopamine β-hydroxylase (Dbh) gene. Embryonic ATP concentrations decreased dramatically, whereas ADP concentrations rose such that the ATP/ADP ratio in the adrenergic-deficient group was nearly 50-fold less than that found in littermate controls by embryonic day 11.5. We also found that cardiac extracellular acidification and oxygen consumption rates were significantly decreased, and mitochondria were significantly larger and more branched in adrenergic-deficient hearts. Notably, however, the mitochondria were intact with well-formed cristae, and there was no significant difference observed in mitochondrial membrane potential. Maternal administration of the adrenergic receptor agonists isoproterenol or l-phenylephrine significantly ameliorated the decreases in ATP observed in Dbh-/- embryos, suggesting that α- and β-adrenergic receptors were effective modulators of ATP concentrations in mouse embryos in vivo. These data demonstrate that adrenergic hormones stimulate cardiac energy metabolism during a critical period of embryonic development.
    Mesh-Begriff(e) Adrenergic Agents/metabolism ; Adrenergic Agents/pharmacology ; Animals ; Autonomic Nervous System Diseases/embryology ; Autonomic Nervous System Diseases/genetics ; Autonomic Nervous System Diseases/metabolism ; Autonomic Nervous System Diseases/physiopathology ; Dopamine beta-Hydroxylase/deficiency ; Dopamine beta-Hydroxylase/genetics ; Dopamine beta-Hydroxylase/metabolism ; Embryo, Mammalian ; Energy Metabolism/drug effects ; Energy Metabolism/genetics ; Epinephrine/metabolism ; Epinephrine/pharmacology ; Female ; Heart/drug effects ; Heart/embryology ; Heart/innervation ; Heart Diseases/embryology ; Heart Diseases/genetics ; Heart Diseases/metabolism ; Isoproterenol/pharmacology ; Maternal-Fetal Exchange/drug effects ; Mice ; Mice, Knockout ; Norepinephrine/deficiency ; Norepinephrine/metabolism ; Norepinephrine/pharmacology ; Pregnancy ; Up-Regulation/drug effects
    Chemische Substanzen Adrenergic Agents ; Dopamine beta-Hydroxylase (EC 1.14.17.1) ; Isoproterenol (L628TT009W) ; Norepinephrine (X4W3ENH1CV) ; Epinephrine (YKH834O4BH)
    Sprache Englisch
    Erscheinungsdatum 2014-12-16
    Erscheinungsland United States
    Dokumenttyp Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 603841-4
    ISSN 1522-1555 ; 0193-1849
    ISSN (online) 1522-1555
    ISSN 0193-1849
    DOI 10.1152/ajpendo.00267.2014
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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