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  • Ovid Technologies (Wolters Kluwer Health)  (7)
  • 1
    Online Resource
    Online Resource
    Abstract 431: Mitochondrial Fission in the Heart is an Adaptation to Increased Energetic Demands: The Role of Physiologic Fragmentation
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation Research Vol. 119, No. suppl_1 ( 2016-07-22)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 119, No. suppl_1 ( 2016-07-22)
    Abstract: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Current paradigms hold that mitochondrial fission and fragmentation are the result of pathologic stresses such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in cardiac impairment, suggesting that fission is important for maintaining normal mitochondrial function. In this study, we identify a novel role for mitochondrial fragmentation as a normal physiological adaptation to increased energetic demand. Using two models of exercise, we demonstrate that “physiologic” mitochondrial fragmentation occurs, results in enhanced mitochondrial function, and is mediated through beta 1-adrenergic receptor signaling. Similar to pathologic fragmentation, physiologic fragmentation is induced by activation of Drp1; however, unlike pathologic fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. To confirm the role of fragmentation as a physiological adaptation to exercise, we inhibited the pro-fission mediator Drp1 in mice using the peptide inhibitor P110 and had mice undergo exercise. Mice treated with P110 had significantly decreased exercise capacity, decreased fragmentation and inactive Drp1 vs controls. To further confirm these findings, we generated cardiac-specific Drp1 KO mice and had them undergo exercise. Mice with cardiac specific Drp1 KO had significantly decreased exercise capacity and abnormally large mitochondria compared to controls. These findings indicate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise and support the still evolving conceptual framework, where fragmentation plays a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.119.suppl_1.431
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1467838-X
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  • 2
    Online Resource
    Online Resource
    Abstract 83: β1 Vs β2 Adrenergic Signaling Differentially Regulates Mitochondrial Dynamics Through Alterations In Calcineurin And Drp1
    Ovid Technologies (Wolters Kluwer Health) ; 2014
    In:  Circulation Research Vol. 115, No. suppl_1 ( 2014-07-18)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 115, No. suppl_1 ( 2014-07-18)
    Abstract: Signal transduction through β1 and β2-adrenergic receptors (ARs) is considered a primary mechanism for regulating cardiovascular function and remodeling. Upon β-AR activation (i.e., physical activity, cardiac pathology) inotropy and chonotropy increase and mitochondria must quickly meet increased energy demand. This suggests that βARs and mitochondria are coupled mechanistically to rapidly respond to the functional and energetic needs of the heart. To investigate the role of β1 vs. β2-AR signaling on mitochondrial dynamics, we compared β1-/- and β2-/- to WT controls. β2-/- had increased mitochondrial fragmentation (increased number and decreased size) by electron microscopy vs. both WT and β1-/-. β2-/- showed altered regulation of mitochondrial fission: increased Drp1 translocation to the mitochondria vs. WT, whereas β1-/- had lower Drp1 translocation. These data suggest differential regulation of fission by βAR signaling, β1 activating and β2 suppressing fission. Since Ca2+-dependent calcineurin is known to activate Drp1 and [Ca2+]i is differentially regulated by β-AR signaling, we examined calcineurin as the bridge between β-AR signaling and Drp1 activation. In β2-/-, both Ca2+ transients and calcineurin activity were increased, suggesting β1-AR/Ca2+/calcinurin-mediated fission. To quantify mitochondrial fragmentation and biogenesis, mitotimer-transfected C2C12 cells were treated with the non-specific β-AR agonist isoproterenol resulting in mitochondrial fragmentation that was inhibited by the β1-antagonist CGP 12177 but not by the ß2-antagonist ICI 118551. Taken together, our data indicate that β1 and β2-AR signaling differentially regulate mitochondrial dynamics in the heart through alterations in [Ca2+] i, leading to calcineurin-induced translocation of Drp1.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.115.suppl_1.83
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2014
    detail.hit.zdb_id: 1467838-X
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  • 3
    Online Resource
    Online Resource
    Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Research Vol. 122, No. 2 ( 2018-01-19), p. 282-295
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 122, No. 2 ( 2018-01-19), p. 282-295
    Abstract: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis. Objective: The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise. Methods and Results: We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity. Conclusions: These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.117.310725
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
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    Online Resource
  • 4
    Online Resource
    Online Resource
    Abstract 242: Mitophagy is Required for Mitochondrial Biogenesis and Myogenic Differentiation of Myoblasts
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Research Vol. 117, No. suppl_1 ( 2015-07-17)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 117, No. suppl_1 ( 2015-07-17)
    Abstract: Myogenesis is a crucial process governing muscle development and homeostasis. Differentiation of primitive myoblasts into mature myotubes requires a metabolic switch to support the increased energetic demand of contractile muscle. Skeletal myoblasts specifically shift from a highly glycolytic state to relying predominantly on oxidative phosphorylation (OXPHOS) upon differentiation. We have found that this phenomenon requires dramatic remodeling of the mitochondrial network involving both mitochondrial clearance and biogenesis. During early myogenic differentiation, autophagy is robustly upregulated and this coincides with DNML1/DRP1-mediated fragmentation and subsequent removal of mitochondria via p62/SQSTM-mediated mitophagy. Mitochondria are then repopulated via PPARGC1A/PGC-1α-mediated biogenesis. Mitochondrial fusion protein OPA1 is then briskly upregulated, resulting in the reformation of mitochondrial networks. The final product is a myotube replete with new mitochondria. Respirometry reveals that the constituents of these newly established mitochondrial networks are better primed for OXPHOS and are more tightly coupled than those in myoblasts. Additionally, we have found that blocking autophagy with various inhibitors during differentiation results in a blockade in myogenic differentiation. Together these data highlight the integral role of autophagy and mitophagy in myogenic differentiation.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.117.suppl_1.242
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467838-X
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    Online Resource
  • 5
    Online Resource
    Online Resource
    Abstract 89: MitoTimer Mouse: a Novel Tool for the Study of Mitochondrial Turnover in vivo
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Research Vol. 117, No. suppl_1 ( 2015-07-17)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 117, No. suppl_1 ( 2015-07-17)
    Abstract: In order to study mitochondrial turnover at the level of a single mitochondrion, our laboratory has developed the MitoTimer protein. Timer is a mutant of DsRed fluorescent protein developed by Terskikh et al. The Timer protein transitions from green fluorescence to a more stable red conformation as it matures over a span of 48 h. Furthermore, the protein is very stable under physiological conditions, insensitive to variations in ionic strength, and changes in pH between 7.0 and 8.0. Notably, Timer maturation from green to red is significantly slowed in deoxygenated buffer, suggesting that molecular oxygen plays a part in fluorophore maturation. We fused the Timer protein with the mitochondrial signal sequence from the cytochrome c oxidase subunit VIII (COX8) to target the protein to the inner membrane of the mitochondria, and further cloned the protein into a construct with a cardiac-restricted α-myosin heavy chain promoter. This construct was used to create the α-MHC MitoTimer mice. Surprisingly, initial analysis of the hearts from these mice reveals a remarkable degree of heterogeneity in the ratio of red-to- green fluorescence of MitoTimer in cardiac tissue. Furthermore, individual mitochondria within cardiomyocytes display a higher red-to-green fluorescence, implying a block in import of newly synthesized MitoTimer that would be caused by the lack of a high membrane potential, indicative of older, dysfunctional mitochondria. Initial studies suggest that these mice represent an elegant tool for the investigation of mitochondrial turnover in the heart.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.117.suppl_1.89
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
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    Online Resource
  • 6
    Online Resource
    Online Resource
    Abstract P3024: Mitochondrial Dysfunction Underlies Sinoatrial Node Dysfunction In Heart Failure With Preserved Ejection Fraction
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Research Vol. 131, No. Suppl_1 ( 2022-08-05)
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. Suppl_1 ( 2022-08-05)
    Abstract: Background: Metabolic comorbidities are frequent in patients with heart failure with preserved ejection fraction (HFpEF). We recently demonstrated that chronotropic incompetence and exercise intolerance are associated with intrinsic sinoatrial (SAN) dysfunction in animal models of HFpEF. However, there are no studies investigating whether metabolic dysfunction in HFpEF can lead to mitochondrial dysfunction in the SAN. Hypothesis: Our recent findings uncovering SAN pacemaker dysfunction in HFpEF upon metabolic stress led us to test the hypothesis that mitochondrial dysfunction may underlie this condition. Methods: Male C57Bl6 mice fed high fat diet (HFD) plus nitric oxide inhibitor (L-NAME) or regular chow served as HFpEF and control, respectively. Optical mapping, transcriptomics, targeted quantitative proteomics of mitochondrial proteins, mitochondrial respiration and reactive oxygen species (ROS) assays were conducted using explanted mouse SAN tissue or isolated pacemaker cells. Results: SAN from HFpEF-verified animals after 20 weeks of HFD+LNAME exhibited prolonged SAN recovery time after pacing (100%; P 〈 0.05). RNA sequencing revealed augmentation of gene clusters related to metabolism (i.e. ucp and pdk4 ) and extracellular matrix expansion (i.e. col, postn and Cilp1 ). Targeted proteomics validated SAN RNA-sequencing findings, showing upregulation of proteins related to ROS scavenging, fatty acid transport and TCA/OXPHOS (i.e. SOD, CPT2 and DHSA/B). Depressed maximal mitochondrial respiration was seen in isolated mitochondria from SAN of HFpEF animals compared to controls (-42%; P 〈 0.05). This was supported by increased generation of mitochondrial ROS in single pacemaker cells from HFpEF SAN (70%; P 〈 0.05). Acute mitochondrial dysfunction induced by a mitochondrial uncoupler (FCCP) elicited a pronounced prolongation of SAN recovery time in HFpEF compared to controls (165%; P 〈 0.05). Conclusion: Our results indicate that mitochondrial function is depressed in SAN from HFpEF animals, and is associated with SAN pacemaker dysfunction. Further studies are required to test cause-and-effect and to evaluate potential therapeutic strategies targeting mitochondrial pathways for HFpEF associated abnormalities of sinus rhythm.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/res.131.suppl_1.P3024
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1467838-X
    Location Call Number Limitation Availability
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    Online Resource
  • 7
    Online Resource
    Online Resource
    Abstract 15584: Mitotimer Protein Reveals Remarkable Macro and Micro Heterogeneity in the Heart; A Novel Tool for Determining Mitochondrial Turnover in the Heart
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Vol. 132, No. suppl_3 ( 2015-11-10)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 132, No. suppl_3 ( 2015-11-10)
    Abstract: In order to study mitochondrial turnover at the level of a single mitochondrion, our laboratory has developed the MitoTimer protein. Timer is a mutant of DsRed fluorescent protein developed by Terskikh et al. The Timer protein transitions from green fluorescence to a more stable red conformation as it matures over a span of 48 h. Furthermore, the protein is very stable under physiological conditions, insensitive to variations in ionic strength, and changes in pH between 7.0 and 8.0. Notably, Timer maturation from green to red is significantly slowed in deoxygenated buffer, suggesting that molecular oxygen plays a part in fluorophore maturation. We created a construct that fused the Timer protein cDNA with the inner mitochondrial membrane signal sequence and placed it under the control of the cardiac-restricted α-myosin heavy chain promoter. This construct was used to create the α-MHC MitoTimer mice. Surprisingly, initial analysis of the hearts from these mice demonstrated a high degree of heterogeneity in the ratio of red-to-green fluorescence of MitoTimer in cardiac tissue, revealing regions of high and low oxygen tension. Further, individual mitochondria within cardiomyocytes display a higher red-to-green fluorescence relative to fluorescence of the other mitochondria in the cell, implying a block in import of newly synthesized MitoTimer caused by the lack of a high membrane potential, indicative of older, dysfunctional mitochondria. These mitochondria can be isolated and sorted from the heart by flow cytometry for further analysis. Initial studies suggest that these mice represent an elegant tool for the investigation of mitochondrial turnover in the heart.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.132.suppl_3.15584
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1466401-X
    Location Call Number Limitation Availability
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