MITOCHONDRIAL CA2+ TRANSPORT IN HEART CELLS

Summary

Principal Investigator: Shey Shing Sheu
Abstract: The long-term objective of our research is to elucidate mechanisms of mitochondrial Ca2+ transport in cardiac muscle cells under both physiological and pathological conditions. Extensive studies have implicated that mitochondrial Ca2+ play a pivotal role in controlling cellular Ca2+ homeostasis, energy metabolism, and apoptosis. However, little is known about the molecular identities and functional diversities of mitochondrial Ca2+ transporters. Our Central hypothesis is that "cardiac mitochondria contain at least two Ca2+-activated influx mechanisms, a mitochondrial ryanodine receptor that operates most effectively in the lower ranges (<50 ^M) of Ca2+ and a Ca2+ uniporter that operates most effectively in higher ranges of Ca2+. These two Ca2+ transporters sequester Ca2+ proficiently and complementarity for regulating Ca2+ homeostasis, ATP production, and reactive oxygen species generation. These mitochondrial Ca2+- mediated functions are achieved physiologically by a concomitant increase in mitochondrial ADP, serving not only as a substrate for ATP production but also an inhibitor for mitochondrial permeability transition pores. In diseased states, this coordinated interaction between Ca2+ and ADP is disrupted and prone the cells to Ca2+- and oxidative stress-mediated injury and death". The four specific aims are: 1) to further characterize the molecular properties of mitochondrial ryanodine receptor, 2) to evaluate the distinct role of mitochondrial ryanodine receptor and Ca2+ uniporter in Ca2+ regulation, 3) to determine the modulation of mitochondrial Ca2+ uptake by redox environments, and 4) to elucidate the role of mitochondrial Ca2+ and ADP in balancing cellular ATP generation and Ca2+ homeostasis in healthy and cardiomyopathic hearts. Working closely with our collaborators, we will use multidisciplinary approaches encompassing cell biology, biochemistry, biophysics, and molecular biology, to elucidate the molecular and functional characteristicsof mitochondrial Ca2+ influx mechanisms. Recent studies of diseases caused by either mitochondrial DNA mutations or mitochondrial dysfunction all suggest that Ca2+ deregulation is most critical. Some examples of such diseases are cardiomyopthy in chronic heart failure, ischemic heart disease, neurodegenerative diseases, diabetics, obesity, and aging. Therefore, completion of our research aims will not only to have a significant impact on our understanding of basic mechanisms in the etiology of mitochondria-mediated diseases, but also on our strategies in developing the therapeutic means for treating these diseases.
Funding Period: ----------------1985 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Mitochondrial contact sites: their role in energy metabolism and apoptosis
    Dieter G Brdiczka
    Department of Pharmacology and Physiology, Box 711, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Biochim Biophys Acta 1762:148-63. 2006
  2. pmc Overexpression of ryanodine receptor type 1 enhances mitochondrial fragmentation and Ca2+-induced ATP production in cardiac H9c2 myoblasts
    Jin O-Uchi
    Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
    Am J Physiol Heart Circ Physiol 305:H1736-51. 2013
  3. pmc Superoxide flashes in single mitochondria
    Wang Wang
    Laboratories of Cardiovascular Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
    Cell 134:279-90. 2008
  4. pmc Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species
    Tianzheng Yu
    Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Cardiovasc Res 79:341-51. 2008
  5. ncbi The mitochondrial ryanodine receptor in rat heart: a pharmaco-kinetic profile
    Beth A Altschafl
    Department of Physiology, University of Wisconsin Medical School, 601 Science Drive, Madison, WI 53711, USA
    Biochim Biophys Acta 1768:1784-95. 2007
  6. ncbi Targeting antioxidants to mitochondria: a new therapeutic direction
    Shey Shing Sheu
    Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 711, Rochester, NY 14642, USA
    Biochim Biophys Acta 1762:256-65. 2006
  7. ncbi Inhibiting p90 ribosomal S6 kinase prevents (Na+)-H+ exchanger-mediated cardiac ischemia-reperfusion injury
    Naoya Maekawa
    Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, NY, USA
    Circulation 113:2516-23. 2006
  8. pmc Molecular and functional identification of a mitochondrial ryanodine receptor in neurons
    Regina Jakob
    Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, United States
    Neurosci Lett 575:7-12. 2014
  9. ncbi Mechanisms of reduced mitochondrial Ca2+ accumulation in failing hamster heart
    Lin Lin
    Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Box 711, Rochester, NY 14642, USA
    Pflugers Arch 454:395-402. 2007
  10. ncbi Thapsigargin induces biphasic fragmentation of mitochondria through calcium-mediated mitochondrial fission and apoptosis
    Jennifer R Hom
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    J Cell Physiol 212:498-508. 2007

Scientific Experts

  • Thomas E Gunter
  • Robert F Feissner
  • Shey Shing Sheu
  • Shin Young Ryu
  • Gisela Beutner
  • Robert T Dirksen
  • Jennifer Hom
  • Jennifer R Hom
  • Virendra K Sharma
  • Jin O-Uchi
  • Tianzheng Yu
  • Yisang Yoon
  • Regina Jakob
  • Bong Sook Jhun
  • Stephen Hurst
  • Lan Wei
  • Shi Pan
  • Kathleen W Kinnally
  • LIDZA KALIFA
  • Wang Wang
  • Beth A Altschafl
  • Lin Lin
  • Dieter G Brdiczka
  • Naoya Maekawa
  • Robert A Gross
  • Yuntao Duan
  • Ming Chen
  • Godfrey L Smith
  • Takashi Murayama
  • Jongsun Park
  • Polina Gross
  • Sara Bisetto
  • Sarah Kettlewell
  • Hideto Oyamada
  • Karl A Kasischke
  • Gheorghe Salahura
  • David L Hoffman
  • George A Porter
  • Karen L de Mesy Bentley
  • Jeffery D Molkentin
  • Rodrigo A Quintanilla
  • Simona Boncompagni
  • Feliciano Protasi
  • George Porter
  • Elaine A Sia
  • Naina Phadnis
  • Aiwu Cheng
  • Huaqiang Fang
  • Weidong Wang
  • Linda Groom
  • Xianhua Wang
  • Kaitao Li
  • Jinhu Yin
  • Ju Chen
  • Heping Cheng
  • Wanrui Zhang
  • Peidong Han
  • Joseph P Y Kao
  • Edward G Lakatta
  • James L Robotham
  • Mark P Mattson
  • Kunfu Ouyang
  • Ming Zheng
  • Jie Liu
  • Limor Michael
  • Hector H Valdivia
  • Jennifer S Gewandter
  • Dhananjaya Nauduri
  • Jun Ichi Abe
  • Tetsuro Shishido
  • Seigo Itoh
  • Bo Ding
  • M W Anders
  • Burns C Blaxall
  • Dmitry B Zorov
  • Bradford C Berk

Detail Information

Publications22

  1. ncbi Mitochondrial contact sites: their role in energy metabolism and apoptosis
    Dieter G Brdiczka
    Department of Pharmacology and Physiology, Box 711, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Biochim Biophys Acta 1762:148-63. 2006
    ..Furthermore, we describe experiments involving the complex-stabilizing conditions in vitro and in intact cells. At the end, we discuss unsolved problems and opportunities for clinical application of the complex-stabilizing factors...
  2. pmc Overexpression of ryanodine receptor type 1 enhances mitochondrial fragmentation and Ca2+-induced ATP production in cardiac H9c2 myoblasts
    Jin O-Uchi
    Center for Translational Medicine, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
    Am J Physiol Heart Circ Physiol 305:H1736-51. 2013
    ..These results indicate that RyR1 possesses a mitochondrial targeting/retention signal and modulates mitochondrial morphology and Ca(2+)-induced ATP production in cardiac H9c2 myoblasts. ..
  3. pmc Superoxide flashes in single mitochondria
    Wang Wang
    Laboratories of Cardiovascular Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
    Cell 134:279-90. 2008
    ..We propose that superoxide flashes could serve as a valuable biomarker for a wide variety of oxidative stress-related diseases...
  4. pmc Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species
    Tianzheng Yu
    Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Cardiovasc Res 79:341-51. 2008
    ..We investigated the role of mitochondrial fission in high glucose-induced cardiovascular cell injury...
  5. ncbi The mitochondrial ryanodine receptor in rat heart: a pharmaco-kinetic profile
    Beth A Altschafl
    Department of Physiology, University of Wisconsin Medical School, 601 Science Drive, Madison, WI 53711, USA
    Biochim Biophys Acta 1768:1784-95. 2007
    ..These results therefore provide the first direct evidence that a unique RyR occurs in mitochondrial membranes...
  6. ncbi Targeting antioxidants to mitochondria: a new therapeutic direction
    Shey Shing Sheu
    Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 711, Rochester, NY 14642, USA
    Biochim Biophys Acta 1762:256-65. 2006
    ....
  7. ncbi Inhibiting p90 ribosomal S6 kinase prevents (Na+)-H+ exchanger-mediated cardiac ischemia-reperfusion injury
    Naoya Maekawa
    Cardiovascular Research Institute, Department of Medicine, University of Rochester, Rochester, NY, USA
    Circulation 113:2516-23. 2006
    ..Therefore, we hypothesized that inhibiting RSK in cardiomyocytes would prevent NHE1 activation and decrease I/R-mediated injury...
  8. pmc Molecular and functional identification of a mitochondrial ryanodine receptor in neurons
    Regina Jakob
    Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, United States
    Neurosci Lett 575:7-12. 2014
    ....
  9. ncbi Mechanisms of reduced mitochondrial Ca2+ accumulation in failing hamster heart
    Lin Lin
    Department of Pharmacology and Physiology, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Box 711, Rochester, NY 14642, USA
    Pflugers Arch 454:395-402. 2007
    ..In addition to other known impairments of ion transport in sarcoplasmic reticulum and plasma membrane, results from this paper on mitochondrial dysfunctions expand our understanding of the molecular mechanisms leading to heart failure...
  10. ncbi Thapsigargin induces biphasic fragmentation of mitochondria through calcium-mediated mitochondrial fission and apoptosis
    Jennifer R Hom
    Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    J Cell Physiol 212:498-508. 2007
    ..These results suggest that Ca(2+) is involved in controlling mitochondrial morphology via intra-mitochondrial Ca(2+) signaling as well as the apoptotic process...
  11. pmc Morphological dynamics of mitochondria--a special emphasis on cardiac muscle cells
    Jennifer Hom
    Department of Pharmacology and Physiology, Mitochondrial Research and Innovation Group, University of Rochester Medical Center, Rochester, NY 14642, USA
    J Mol Cell Cardiol 46:811-20. 2009
    ..In this review we will cover the recent field of mitochondrial dynamics and its physiological and pathological implications, with a particular emphasis on the experimental and theoretical basis of mitochondrial dynamics in the heart...
  12. pmc Characteristics and possible functions of mitochondrial Ca(2+) transport mechanisms
    Thomas E Gunter
    Department of Biochemistry and Biophysics and Mitochondrial Research and Innovation Group, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA
    Biochim Biophys Acta 1787:1291-308. 2009
    ..The characteristics of these mechanisms of Ca(2+) transport and a discussion of how they might function are described in this paper...
  13. pmc The permeability transition pore controls cardiac mitochondrial maturation and myocyte differentiation
    Jennifer R Hom
    Department of Pediatrics Division of Cardiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Dev Cell 21:469-78. 2011
    ..Furthermore, myocyte differentiation was inhibited and enhanced with oxidant and antioxidant treatment, respectively, suggesting that redox-signaling pathways lie downstream of mitochondria to regulate cardiac myocyte differentiation...
  14. pmc Distinctive characteristics and functions of multiple mitochondrial Ca2+ influx mechanisms
    Shi Pan
    Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA
    Sci China Life Sci 54:763-9. 2011
    ..Their potential physiological and pathological implications are also discussed...
  15. pmc Mitochondrial superoxide flashes: metabolic biomarkers of skeletal muscle activity and disease
    Lan Wei
    University of Rochester Medical Center, Department of Pharmacology and Physiology, Rochester, NY 14642, USA
    FASEB J 25:3068-78. 2011
    ..Together, these results demonstrate that mSOF activity is a highly sensitive biomarker of mitochondrial respiration and the cellular metabolic state of muscle during physiological activity and pathological oxidative stress..
  16. pmc Single channel characterization of the mitochondrial ryanodine receptor in heart mitoplasts
    Shin Young Ryu
    Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642, USA
    J Biol Chem 286:21324-9. 2011
    ....
  17. pmc Crosstalk signaling between mitochondrial Ca2+ and ROS
    Robert F Feissner
    Mitochondrial Research and Innovation Group and Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, NY 14642, USA
    Front Biosci (Landmark Ed) 14:1197-218. 2009
    ..We present a model for crosstalk between Ca2+ and ROS signaling pathways within mitochondrial microdomains...
  18. pmc Mitochondrial ryanodine receptors and other mitochondrial Ca2+ permeable channels
    Shin Young Ryu
    Department of Pharmacology and Physiology, and Mitochondrial Research Innovation Group, University of Rochester Medical Center, Rochester, NY 14642, USA
    FEBS Lett 584:1948-55. 2010
    ..Here, we discuss recent progresses in the biophysical and electrophysiological characterization of several distinct mitochondrial Ca(2+) channels...
  19. pmc Evidence for a role of FEN1 in maintaining mitochondrial DNA integrity
    LIDZA KALIFA
    Department of Biology, University of Rochester, NY 14627, United States
    DNA Repair (Amst) 8:1242-9. 2009
    ..Our findings demonstrate that Rad27p/FEN1 is localized in the mitochondrial compartment of both yeast and mice and that Rad27p has a significant role in maintaining mtDNA integrity...
  20. pmc Regulation of mitochondrial fission by intracellular Ca2+ in rat ventricular myocytes
    Jennifer Hom
    Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
    Biochim Biophys Acta 1797:913-21. 2010
    ..These results suggest that Ca2+, an important regulator of muscle contraction and energy generation, also dynamically regulates mitochondrial morphology and ROS generation in cardiac myocytes...