1. Medicine
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Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

  1. Ying Ann Chiao  Is a corresponding author
  2. Huiliang Zhang
  3. Mariya Sweetwyne
  4. Jeremy Whitson
  5. Ying Sonia Ting
  6. Nathan Basisty
  7. Lindsay K Pino
  8. Ellen Quarles
  9. Ngoc-Han Nguyen
  10. Matthew D Campbell
  11. Tong Zhang
  12. Matthew J Gaffrey
  13. Gennifer Merrihew
  14. Lu Wang
  15. Yongping Yue
  16. Dongsheng Duan
  17. Henk L Granzier
  18. Hazel H Szeto
  19. Wei-Jun Qian
  20. David Marcinek
  21. Michael J MacCoss
  22. Peter Rabinovitch  Is a corresponding author
  1. Oklahoma Medical Research Foundation, United States
  2. University of Washington, United States
  3. Buck Institute for Research on Aging, United States
  4. Pacific Northwest National Laboratory, United States
  5. University of Missouri, United States
  6. University of Arizona, United States
  7. Social Profit Network, United States
Research Article
  • Cited 12
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Cite this article as: eLife 2020;9:e55513 doi: 10.7554/eLife.55513

Abstract

Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets for cardiac aging.

Data availability

Data file for metabolomic analysis (Table S1) and statistics of all proteins identified by proteomic analysis (Table S3) have been provided as supplementary materials.The raw mass spec files for proteomics analysis of S-glutathionylation were uploaded to MassIVE and can be accessed via the following link ftp://massive.ucsd.edu/MSV000085329/The raw mass spectrometry files for global proteomic analysis were uploaded to MassIVE and can be accessed via the following link ftp://massive.ucsd.edu/MSV000084961/The image files for ROS (Fig 2a and b) and senescence (Fig 4b and c) analyses can be accessed via the following link and were also included as supporting zip documents. https://www.dropbox.com/sh/0r50ew6xnpunc3t/AAA_HbJ0fQwhOUpDbI9Oq07va?dl=0

Article and author information

Author details

  1. Ying Ann Chiao

    Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, OKlahom City, United States
    For correspondence
    Ann-Chiao@omrf.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1256-4335
  2. Huiliang Zhang

    Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mariya Sweetwyne

    Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeremy Whitson

    Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ying Sonia Ting

    Genome Science, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nathan Basisty

    Buck Institute for Research on Aging, Novato, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lindsay K Pino

    Genome Science, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ellen Quarles

    Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Ngoc-Han Nguyen

    Pathology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Matthew D Campbell

    Radiology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Tong Zhang

    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Matthew J Gaffrey

    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Gennifer Merrihew

    Genome Science, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Lu Wang

    Environmental and Occupational Health Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Yongping Yue

    Molecular Microbiology and Immunology, University of Missouri, Columbia, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Dongsheng Duan

    Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Henk L Granzier

    Cellular and Molecular Medicine, University of Arizona, Tucson, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9516-407X
  18. Hazel H Szeto

    Social Profit Network, Menlo Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Wei-Jun Qian

    Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. David Marcinek

    Radiology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Michael J MacCoss

    Department of Genome Sciences, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Peter Rabinovitch

    Pathology, University of Washington, Seattle, United States
    For correspondence
    petersr@uw.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

Glenn Foundation for Medical Research (Glenn/AFAR Postdoctoral Fellowship Program for Translational Research on Aging)

  • Ying Ann Chiao

National Institute on Aging (5T32AG000057 Training Grant)

  • Ying Ann Chiao

National Institute on Aging (K99/R00 AG051735)

  • Ying Ann Chiao

National Institute on Aging (P01 AG001751)

  • Peter Rabinovitch

National Institute on Aging (P30 AG013280)

  • Peter Rabinovitch

Glenn Foundation for Medical Research (Glenn/AFAR Postdoctoral Fellowship Program for Translational Research on Aging)

  • Huiliang Zhang

American Heart Association (CDA 19CDA34660311)

  • Huiliang Zhang

National Heart, Lung, and Blood Institute (R35HL144998)

  • Henk L Granzier

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were handled according to the guidelines of the Institutional Animal Care and Use Committee of the University of Washington and approved IACUC Protocol # 2174-23 . Mice were housed at 20ºC in an AAALAC accredited facility under Institutional Animal Care Committee supervision.

Reviewing Editor

  1. Jan Gruber, Yale-NUS College, Singapore

Publication history

  1. Received: January 28, 2020
  2. Accepted: July 7, 2020
  3. Accepted Manuscript published: July 10, 2020 (version 1)
  4. Version of Record published: July 23, 2020 (version 2)

Copyright

© 2020, Chiao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

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    Mieradilijiang Abudupataer et al.
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    Background:

    Bicuspid aortic valve (BAV) is the most common congenital cardiovascular disease in general population and is frequently associated with the development of thoracic aortic aneurysm (TAA). There is no effective strategy to intervene with TAA progression due to an incomplete understanding of the pathogenesis. Insufficiency of NOTCH1 expression is highly related to BAV-TAA, but the underlying mechanism remains to be clarified.

    Methods:

    A comparative proteomics analysis was used to explore the biological differences between non-diseased and BAV-TAA aortic tissues. A microfluidics-based aorta smooth muscle-on-a-chip model was constructed to evaluate the effect of NOTCH1 deficiency on contractile phenotype and mitochondrial dynamics of human aortic smooth muscle cells (HAoSMCs).

    Results:

    Protein analyses of human aortic tissues showed the insufficient expression of NOTCH1 and impaired mitochondrial dynamics in BAV-TAA. HAoSMCs with NOTCH1-knockdown exhibited reduced contractile phenotype and were accompanied by attenuated mitochondrial fusion. Furthermore, we identified that mitochondrial fusion activators (leflunomide and teriflunomide) or mitochondrial fission inhibitor (Mdivi-1) partially rescued the disorders of mitochondrial dynamics in HAoSMCs derived from BAV-TAA patients.

    Conclusions:

    The aorta smooth muscle-on-a-chip model simulates the human pathophysiological parameters of aorta biomechanics and provides a platform for molecular mechanism studies of aortic disease and related drug screening. This aorta smooth muscle-on-a-chip model and human tissue proteomic analysis revealed that impaired mitochondrial dynamics could be a potential therapeutic target for BAV-TAA.

    Funding:

    National Key R and D Program of China, National Natural Science Foundation of China, Shanghai Municipal Science and Technology Major Project, Shanghai Science and Technology Commission, and Shanghai Municipal Education Commission.

    1. Medicine
    Elisabeth Gludovacz et al.
    Research Article Updated

    Background:

    Excessive plasma histamine concentrations cause symptoms in mast cell activation syndrome, mastocytosis, or anaphylaxis. Anti-histamines are often insufficiently efficacious. Human diamine oxidase (hDAO) can rapidly degrade histamine and therefore represents a promising new treatment strategy for conditions with pathological histamine concentrations.

    Methods:

    Positively charged amino acids of the heparin-binding motif of hDAO were replaced with polar serine or threonine residues. Binding to heparin and heparan sulfate, cellular internalization and clearance in rodents were examined.

    Results:

    Recombinant hDAO is rapidly cleared from the circulation in rats and mice. After mutation of the heparin-binding motif, binding to heparin and heparan sulfate was strongly reduced. The double mutant rhDAO-R568S/R571T showed minimal cellular uptake. The short α-distribution half-life of the wildtype protein was eliminated, and the clearance was significantly reduced in rodents.

    Conclusions:

    The successful decrease in plasma clearance of rhDAO by mutations of the heparin-binding motif with unchanged histamine-degrading activity represents the first step towards the development of rhDAO as a first-in-class biopharmaceutical to effectively treat diseases characterized by excessive histamine concentrations in plasma and tissues.

    Funding:

    Austrian Science Fund (FWF) Hertha Firnberg program grant T1135 (EG); Sigrid Juselius Foundation, Medicinska Understödsförening Liv och Hälsa rft (TAS and SeV).