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Sherine Swee Lin Chan

Title
InstitutionMedical University of South Carolina
DepartmentCOP Drug Discovery and Biomedical Sciences - MUSC Campus
AddressP.O. Box MSC140
QE219A
43 Sabin St.
Phone843-792-6095
Fax843-792-2620
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    Collapse Overview 
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    Our mission is to understand how mitochondrial defects give rise to cellular dysfunction and disease. This is not an easy task, as the mitochondrion performs many essential functions, the most important being the production of most of the energy for the cell. Defects in any of the approximately 1,500 mitochondrial proteins can lead to pathological states such as neurodegeneration and cancer. In addition to genetic defects, mitochondrial dysfunction can arise from contact with many environmental agents and drug treatments. Mitochondria contain multiple copies of their own small, circular genome (mitochondrial DNA, mtDNA). Recently, investigators reported that 1 in 5 healthy humans harbor a pathogenic mtDNA mutation. Further complicating the understanding of mitochondrial diseases are issues related to mtDNA copy number in different tissues and different cellular states, levels of mtDNA mutations within cells (known as heteroplasmy), tissue differences in mitochondrial needs, and wide variability in disease presentation and onset of disease despite the same disease mutation.

    We use several diverse in vitro and in vivo methods to analyze mitochondrial dysfunction. In particular, we are using the zebrafish as a model for mitochondrial diseases. The zebrafish (Danio rerio) is an important vertebrate model organism, offering many advantages for understanding basic biological processes. Breeding pairs can produce hundreds of embryos that develop outside of the mother and are frequently used in high-throughput drug screens. The use of zebrafish embryos and larvae for environmental agent testing is also well established. Furthermore, zebrafish embryos can be genetically manipulated, and because these embryos are transparent, development can be monitored and phenotypic changes can be scored easily.

    There are no cures or effective long-term treatments for mitochondrial diseases. To fulfill our long-term goals of developing therapeutic treatments and new biomarkers for the early detection of mitochondrial disease, we are investigating pathways that are important in the development of mitochondrial disease, and the role of environmental and drug modifiers on mitochondrial function.

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    Mitochondria, mitochondrial disease, mitochondrial DNA, zebrafish, drug discovery, embryogenesis, aging, neurological disease, cardiovascular disease high-throughput in vivo methods

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    Collapse selected publications
    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Chan SSL. Inherited mitochondrial genomic instability and chemical exposures. Toxicology. 2017 11 01; 391:75-83. PMID: 28756246.
      View in: PubMed
    2. Rahn JJ, Bestman JE, Stackley KD, Chan SS. Zebrafish lacking functional DNA polymerase gamma survive to juvenile stage, despite rapid and sustained mitochondrial DNA depletion, altered energetics and growth. Nucleic Acids Res. 2015 Dec 02; 43(21):10338-52. PMID: 26519465.
      View in: PubMed
    3. Jayasundara N, Kozal JS, Arnold MC, Chan SS, Di Giulio RT. High-Throughput Tissue Bioenergetics Analysis Reveals Identical Metabolic Allometric Scaling for Teleost Hearts and Whole Organisms. PLoS One. 2015; 10(9):e0137710. PMID: 26368567.
      View in: PubMed
    4. Bohovych I, Fernandez MR, Rahn JJ, Stackley KD, Bestman JE, Anandhan A, Franco R, Claypool SM, Lewis RE, Chan SS, Khalimonchuk O. Metalloprotease OMA1 Fine-tunes Mitochondrial Bioenergetic Function and Respiratory Supercomplex Stability. Sci Rep. 2015 Sep 14; 5:13989. PMID: 26365306.
      View in: PubMed
    5. Whitaker RM, Stallons LJ, Kneff JE, Alge JL, Harmon JL, Rahn JJ, Arthur JM, Beeson CC, Chan SL, Schnellmann RG. Urinary mitochondrial DNA is a biomarker of mitochondrial disruption and renal dysfunction in acute kidney injury. Kidney Int. 2015 Dec; 88(6):1336-1344. PMID: 26287315.
      View in: PubMed
    6. Bestman JE, Stackley KD, Rahn JJ, Williamson TJ, Chan SS. The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos. Differentiation. 2015 Mar-Apr; 89(3-4):51-69. PMID: 25771346.
      View in: PubMed
    7. Ghosh A, Trivedi PP, Timbalia SA, Griffin AT, Rahn JJ, Chan SS, Gohil VM. Copper supplementation restores cytochrome c oxidase assembly defect in a mitochondrial disease model of COA6 deficiency. Hum Mol Genet. 2014 Jul 01; 23(13):3596-606. PMID: 24549041.
      View in: PubMed
    8. Bohovych I, Chan SSL, Khalimonchuk O. Mitochondrial protein quality control: the mechanisms guarding mitochondrial health. Antioxidants and Redox Signaling. 2014.
    9. Rahn JJ, Bestman JE, Josey BJ, Inks ES, Stackley KD, Rogers CE, Chou CJ, Chan SS. Novel Vitamin K analogs suppress seizures in zebrafish and mouse models of epilepsy. Neuroscience. 2014 Feb 14; 259:142-54. PMID: 24291671.
      View in: PubMed
    10. Rahn JJ, Stackley KD, Chan SS. Opa1 is required for proper mitochondrial metabolism in early development. PLoS One. 2013; 8(3):e59218. PMID: 23516612.
      View in: PubMed
    11. Stackley KD, Beeson CC, Rahn JJ, Chan SS. Bioenergetic profiling of zebrafish embryonic development. PLoS One. 2011; 6(9):e25652. PMID: 21980518.
      View in: PubMed
    12. Zhang L, Chan SS, Wolff DJ. Mitochondrial disorders of DNA polymerase ? dysfunction: from anatomic to molecular pathology diagnosis. Arch Pathol Lab Med. 2011 Jul; 135(7):925-34. PMID: 21732785.
      View in: PubMed
    13. Chan SS, Naviaux RK, Basinger AA, Casas KA, Copeland WC. De novo mutation in POLG leads to haplotype insufficiency and Alpers syndrome. Mitochondrion. 2009 Sep; 9(5):340-5. PMID: 19501198.
      View in: PubMed
    14. Kasiviswanathan R, Longley MJ, Chan SS, Copeland WC. Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication. J Biol Chem. 2009 Jul 17; 284(29):19501-10. PMID: 19478085.
      View in: PubMed
    15. Chan SS, Copeland WC. Functional analysis of mutant mitochondrial DNA polymerase proteins involved in human disease. Methods Mol Biol. 2009; 554:59-72. PMID: 19513667.
      View in: PubMed
    16. Chan SS, Copeland WC. DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. Biochim Biophys Acta. 2009 May; 1787(5):312-9. PMID: 19010300.
      View in: PubMed
    17. Chan SS, Santos JH, Meyer JN, Mandavilli BS, Cook DL, McCash CL, Kissling GE, Nyska A, Foley JF, van Houten B, Copeland WC, Walker VE, Witt KL, Bishop JB. Mitochondrial toxicity in hearts of CD-1 mice following perinatal exposure to AZT, 3TC, or AZT/3TC in combination. Environ Mol Mutagen. 2007 Apr-May; 48(3-4):190-200. PMID: 16395692.
      View in: PubMed
    18. Chan SS, Longley MJ, Copeland WC. Modulation of the W748S mutation in DNA polymerase gamma by the E1143G polymorphismin mitochondrial disorders. Hum Mol Genet. 2006 Dec 01; 15(23):3473-83. PMID: 17088268.
      View in: PubMed
    19. Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK. Molecular diagnosis of Alpers syndrome. J Hepatol. 2006 Jul; 45(1):108-16. PMID: 16545482.
      View in: PubMed
    20. Lewis W, Day BJ, Kohler JJ, Hosseini SH, Chan SS, Green EC, Haase CP, Keebaugh ES, Long R, Ludaway T, Russ R, Steltzer J, Tioleco N, Santoianni R, Copeland WC. Decreased mtDNA, oxidative stress, cardiomyopathy, and death from transgenic cardiac targeted human mutant polymerase gamma. Lab Invest. 2007 Apr; 87(4):326-35. PMID: 17310215.
      View in: PubMed
    21. Chan SS, Longley MJ, Naviaux RK, Copeland WC. Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers syndrome. DNA Repair (Amst). 2005 Dec 08; 4(12):1381-9. PMID: 16181814.
      View in: PubMed
    22. Chan SS, Longley MJ, Copeland WC. The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. J Biol Chem. 2005 Sep 09; 280(36):31341-6. PMID: 16024923.
      View in: PubMed
    23. Chan SS, Kent GN, Will RK. A sensitive assay for the measurement of serum chondroitin sulfate 3B3(-) epitope levels in human rheumatic diseases. Clin Exp Rheumatol. 2001 Sep-Oct; 19(5):533-40. PMID: 11579712.
      View in: PubMed
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