Up-to-date link to publications on Pubmed:
http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/40309258/?sort=date&direction=descending
Link to Sherine Chan Lab on ZFIN:
https://zfin.org/ZDB-LAB-150729-1
Publications resulting from research performed at the Medical University of South Carolina
Cahill T, da Silveira WA, Renaud L, Williamson T, Wang H, Chung D, Overton I, Chan SSL, Hardiman G. Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model. Cells. 2021. 10(4):906.
Li X*, Himes RA, Prosser LC, Christie CF, Watt E, Edwards SF, Metcalf C, West P, Wilcox K, Chan SSL*, Chou CJ*. Discovery of the first Vitamin K analog as a potential treatment of pharmacoresistant seizures. J Med Chem. 2020. PMID: 32390424
Li X, Jiang Y, Peterson YK, Tongqiang X, Himes RA, Xin L, Yin G, Inks ES, Dolloff N, Halene S, Chan SSL, Chou CJ. Design of hydrazide-bearing HDACIs based on panobinostat and their p53 and FLT3-ITD dependency in anti-leukemia activity. J Med Chem. 2020. PMID: 32321249.
Adeluyi A, Guerin L, Fisher ML, Galloway A, Cole RD, Chan SSL, Wyatt MD, Davis SW, Freeman LR, Ortinski PI, Turner JR. Microglia morphology and proinflammatory signaling in the nucleus accumbens during nicotine withdrawal. Science Advances. 2019 Oct;5(10):eaax7031. PMCID: PMC6785260
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785260/
Sokol AM, Uszczynska-Ratajczak B, Collins MM, Bazala M, Topf U, Sugunan S, Guenther S, Kuenne C, Graumann J, Chan SSL, Stainier DYR, Chacinska A. Loss of the life-essential paralogue of mia40 leads to hepato-pancreatic insufficiency in the zebrafish. PLoS Genetics. 14(11):e1007743
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007743
Jing R, Corbett, JL, Cai J, Beeson GC, Beeson CC, Chan SSL, Dimmock DP, Lazcares L, Geurts AM, Lemasters JJ, Duncan SA. A Drug Screen using iPSC-Derived Hepatocytes reveals nicotinamide adenine dinucleotide (NAD) as a Potential Treatment for a Mitochondrial DNA Depletion Syndrome. 2018. Cell Reports. 25(6): 1469-1484.
https://www.sciencedirect.com/science/article/pii/S2211124718316127?via%3Dihub
Llanos PJ, Andrijauskaite K, Rubinstein MP, Chan SSL. Investigation of Zebrafish Larvae Behavior as Precursor for Suborbital Flights: Feasibility Study. 2018. Gravitational and Space Research, 6(1):37-57.
http://gravitationalandspacebiology.org/index.php/journal/article/view/812
Cover: http://gravitationalandspacebiology.org/index.php/journal
Soma S, Latimer AJ, Chun H, Vicary AC, Timbalia SA, Boulet A, Rahn JJ, Chan SSL, Leary SC, Kim BE, Gitlin JD, Gohil VM. Elesclomol restores mitochondrial function in genetic models of copper deficiency. Proc Natl Acad Sci U S A. 2018. In Press.
http://www.pnas.org/cgi/pmidlookup?view=long&pmid=30038027
Chan SSL. Inherited mitochondrial genomic instability and chemical exposures. 2017. Toxicology. 391:75-83.
http://www.sciencedirect.com/science/article/pii/S0300483X17302135
Meyer JN, Chan SSL. Sources, mechanisms, and consequences of chemical-induced mitochondrial toxicity. 2017. Toxicology. 391:2-4.
http://www.sciencedirect.com/science/article/pii/S0300483X17301695
Chan SSL, Williamson TJ. Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants. Will Y, Dykens JA, editors. USA: Wiley and Sons; 2017. Detection of Mitochondrial Toxicity using Zebrafish. p323-346.
Majchrzak K, Nelson MH, Bowers JS, Bailey SR, Wyatt MM, Wrangle JM, Rubinstein MP, Varela JC, Li Z, Himes RA, Chan SSL, Paulos CM. β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity. JCI Insight. 2017. 2(8):e90547.
https://insight.jci.org/articles/view/90547
Rahn JJ, Bestman JE, Stackley KD, Chan SSL. Zebrafish lacking functional DNA polymerase gamma survive to juvenile stage, despite rapid and sustained mitochondrial DNA depletion, altered energetics and growth. 2015. Nucleic Acids Research. 43 (21): 10338-10352.
http://nar.oxfordjournals.org/content/43/21/10338.full
Bestman JE, Stackley KD, Rahn JJ, Williamson TJ, Chan SSL. The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos. 2015. Differentiation. 89(3-4):51-69.
http://www.sciencedirect.com/science/article/pii/S0301468115000134
Bohovych I, Chan SSL, Khalimonchuk O. Mitochondrial protein quality control: the mechanisms guarding mitochondrial health. Antioxidants and Redox Signaling. 2015. 22(12):977-94.
http://online.liebertpub.com/doi/abs/10.1089/ars.2014.6199
Jayasundara N, Kozal JS, Arnold MC, Chan SSL, Di Giulio RT. High-throughput tissue bioenergetics analysis reveals equivalent metabolic allometric scaling for teleost hearts and whole organisms. 2015. PLoS ONE. 10(9): e0137710.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137710
Whitaker RM, Stallons LJ, Kneff JE, Harmon JL, Rahn JJ, Arthur JM, Beeson CC, Chan SSL and Schnellmann RG. Urinary mitochondrial DNA predicts progression of renal dysfunction and mitochondrial disruption in acute kidney injury. Kidney International. 2015. 88(6):1336-1344.
http://www.sciencedirect.com/science/article/pii/S0085253815610481
Bohovych I, Fernandez MR, Rahn JJ, Stackley KD, Bestman JE, Anandhan A, Franco R, Claypool SM, Lewis RE, Chan SSL, Khalimonchuk O. Metalloprotease OMA1 is Involved in Fine-tuning of Mitochondrial Bioenergetic Function and Respiratory Supercomplex Stability. 2015. Scientific Reports. 5:13989.
http://www.nature.com/articles/srep13989
Rahn JJ, Bestman JE, Josey BJ, Inks ES, Stackley KD, Rogers CE, Chou CJ*, Chan SSL*. Novel Vitamin K analogues suppress seizures in zebrafish and mouse models of epilepsy. 2014. Neuroscience. 259: 142-154.
http://www.sciencedirect.com/science/article/pii/S0306452213009871
Ghosh A, Trivedi PP, Timbalia, SA, Griffin AT, Rahn JJ, Chan SSL, Gohil VM. Copper supplementation restores cytochrome c oxidase assembly defect in a mitochondrial disease model of COA6 deficiency. 2014. Human Molecular Genetics, 23(13):3596-3606.
http://hmg.oxfordjournals.org/content/23/13/3596
Rahn JJ, Stackley KD, Chan SSL. Opa1 is required for proper mitochondrial metabolism in early development. 2013. PLoS ONE, 8(3):e59218. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0059218
Stackley KD, Beeson CC, Rahn JJ, Chan SSL. Bioenergetic profiling of zebrafish embryonic development. 2011. PLoS ONE, 6(9): e25652. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0025652
Zhang L*, Chan SSL*, Wolff D. Mitochondrial Disorders of DNA Polymerase Gamma Dysfunction: From Anatomic to Molecular Pathology Diagnosis. 2011. Archives of Pathology and Laboratory Medicine. 135(7):925-34. PMC3158670. * co-first authors http://www.ncbi.nlm.nih.gov/pubmed/21732785
Summary of research prior to joining the Medical University of South Carolina
Oxidative stress and mtDNA mutagenesis in male infertility
Under the mentorship of Dr. Jim Cummins at the Vet. School, Murdoch University we investigated the roles of mitochondrial DNA (mtDNA) mutagenesis and reactive oxygen species (ROS) in male infertility. In collaboration with a major fertility clinic in Western Australia, we measured mitochondrial dysfunction (such as mtDNA mutations, sensitivity to ROS) in spermatazoa from a cohort of infertile men. We found that environmental oxidants could promote the formation of the common mtDNA deletion associated with aging.
New biomarkers for early cartilage degradation in arthritis
Traditionally, radiological measures are used to determine progression of arthritis, but more sensitive methods are needed. For graduate school, I joined the Department of Medicine at the University of Western Australia to work with Drs. Neil Kent, Fiona Lake, and Robert Will at UWA. We developed a number of sensitive assays utilizing new biomarkers of cartilage turnover (Chan et al., Clin Exp Rheumatol, 2001), which were validated against large cohorts of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, twin, exercise, and control populations. Differences in aggrecan processing correlated with disease phenotype, drug treatment, and radiological measures.
Studies of the mtDNA polymerase
For my postdoctoral fellowship, I joined the lab of Dr. Bill Copeland at NIEHS/NIH, whose lab was the first to clone and characterize the human mtDNA polymerase. A diverse range of techniques were utilized to understand mitochondrial dysfunction in disease. As DNA polymerase gamma is the only known DNA polymerase within the mitochondrion, it is absolutely essential for faithful replication, proofreading, and repair of mtDNA. Alpers syndrome is a mtDNA depletion syndrome leading to fatal neurohepatopathy in children. We collaborated with Dr. Robert Naviaux at UCSD, who was the first to link Alpers syndrome with POLG mutations. We screened a cohort of Alpers syndrome patients and found five novel mutations in the catalytic subunit of DNA polymerase gamma (encoded by POLG; Nguyen et al., J Hepatol, 2006). Furthermore, each patient had at least one POLG allele containing either the A467T or W748S mutations, which are the two most common disease mutations in POLG (Chan and Copeland, BBA, 2009). As a result, screening for A467T now constitutes the most rapid and sensitive test for confirming the clinical diagnosis of Alpers syndrome.
Patients with the A467T mutation can develop a range of different mitochondrial diseases. Biochemical characterization of the recombinant A467T protein revealed that the A467T mutation disrupts both normal enzyme catalysis and binding of the catalytic subunit of DNA polymerase gamma to its accessory subunit (Chan et al., J Biol Chem, 2005). We also analyzed fibroblasts from patients carrying the POLG A467T mutation in trans with either a POLG stop codon or intronic frame shift mutation, and showed that transcripts containing the stop codon or frame shift mutation undergo nonsense-mediated decay (Chan et al., DNA Repair, 2005; Chan et al., Mitochondrion, 2009). These events ensured that virtually all POLG protein in the cell derived from the A467T allele, leading to haplotype insufficiency and severe Alpers syndrome.
The second most common POLG mutation, W748S, is generally found in cis with the E1143G polymorphism. It had been a point of contention as to whether polymorphisms participate in the disease process. Using biochemical and structural methods, we showed that the E1143G SNP partially rescues the W748S defect. However, the E1143G SNP renders the protein less stable, thus contributing to mitochondrial dysfunction (Chan et al., Hum Mol Genet, 2006). We have also characterized POLG disease mutations in other regions of the mtDNA polymerase (Kasiviswanathan et al., JBC 2009; Chan and Copeland, Methods Mol Biol, 2009).
A mouse model of mitochondrial toxicity - perinatal exposure to POLG/HIV inhibitors
Pregnant HIV-infected women are often treated with nucleoside reverse transcriptase inhibitors (NRTIs) to prevent vertical transmission of HIV to their children. Unfortunately, these NRTIs also inhibit POLG. In a multi-center study focused on mitochondrial toxicity following perinatal exposure to NRTIs, we showed that AZT-3TC caused persistent mtDNA lesions. Furthermore, this was gender specific, as mtDNA lesions persisted only in female pups after the treatment period (Chan et al., Environ Mol Mutagen, 2007).
A transgenic mouse model of POLG mitochondrial disease
The Y955C mutation in POLG causes autosomal dominant progressive external ophthalmoplegia in humans. We collaborated with Dr. William Lewis (Emory University), whose lab developed a transgenic heart specific Y955C POLG mouse model. These transgenic mice showed mtDNA depletion, increased oxidative stress, cardiomyopathy and reduced lifespan (Lewis et al., Lab Invest, 2007). This is the first mouse model using a known disease mutation in POLG, and pathophysiologically links mtDNA depletion and oxidative stress to defects in POLG.
http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/40309258/?sort=date&direction=descending
Link to Sherine Chan Lab on ZFIN:
https://zfin.org/ZDB-LAB-150729-1
Publications resulting from research performed at the Medical University of South Carolina
Cahill T, da Silveira WA, Renaud L, Williamson T, Wang H, Chung D, Overton I, Chan SSL, Hardiman G. Induced Torpor as a Countermeasure for Low Dose Radiation Exposure in a Zebrafish Model. Cells. 2021. 10(4):906.
Li X*, Himes RA, Prosser LC, Christie CF, Watt E, Edwards SF, Metcalf C, West P, Wilcox K, Chan SSL*, Chou CJ*. Discovery of the first Vitamin K analog as a potential treatment of pharmacoresistant seizures. J Med Chem. 2020. PMID: 32390424
Li X, Jiang Y, Peterson YK, Tongqiang X, Himes RA, Xin L, Yin G, Inks ES, Dolloff N, Halene S, Chan SSL, Chou CJ. Design of hydrazide-bearing HDACIs based on panobinostat and their p53 and FLT3-ITD dependency in anti-leukemia activity. J Med Chem. 2020. PMID: 32321249.
Adeluyi A, Guerin L, Fisher ML, Galloway A, Cole RD, Chan SSL, Wyatt MD, Davis SW, Freeman LR, Ortinski PI, Turner JR. Microglia morphology and proinflammatory signaling in the nucleus accumbens during nicotine withdrawal. Science Advances. 2019 Oct;5(10):eaax7031. PMCID: PMC6785260
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785260/
Sokol AM, Uszczynska-Ratajczak B, Collins MM, Bazala M, Topf U, Sugunan S, Guenther S, Kuenne C, Graumann J, Chan SSL, Stainier DYR, Chacinska A. Loss of the life-essential paralogue of mia40 leads to hepato-pancreatic insufficiency in the zebrafish. PLoS Genetics. 14(11):e1007743
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007743
Jing R, Corbett, JL, Cai J, Beeson GC, Beeson CC, Chan SSL, Dimmock DP, Lazcares L, Geurts AM, Lemasters JJ, Duncan SA. A Drug Screen using iPSC-Derived Hepatocytes reveals nicotinamide adenine dinucleotide (NAD) as a Potential Treatment for a Mitochondrial DNA Depletion Syndrome. 2018. Cell Reports. 25(6): 1469-1484.
https://www.sciencedirect.com/science/article/pii/S2211124718316127?via%3Dihub
Llanos PJ, Andrijauskaite K, Rubinstein MP, Chan SSL. Investigation of Zebrafish Larvae Behavior as Precursor for Suborbital Flights: Feasibility Study. 2018. Gravitational and Space Research, 6(1):37-57.
http://gravitationalandspacebiology.org/index.php/journal/article/view/812
Cover: http://gravitationalandspacebiology.org/index.php/journal
Soma S, Latimer AJ, Chun H, Vicary AC, Timbalia SA, Boulet A, Rahn JJ, Chan SSL, Leary SC, Kim BE, Gitlin JD, Gohil VM. Elesclomol restores mitochondrial function in genetic models of copper deficiency. Proc Natl Acad Sci U S A. 2018. In Press.
http://www.pnas.org/cgi/pmidlookup?view=long&pmid=30038027
Chan SSL. Inherited mitochondrial genomic instability and chemical exposures. 2017. Toxicology. 391:75-83.
http://www.sciencedirect.com/science/article/pii/S0300483X17302135
Meyer JN, Chan SSL. Sources, mechanisms, and consequences of chemical-induced mitochondrial toxicity. 2017. Toxicology. 391:2-4.
http://www.sciencedirect.com/science/article/pii/S0300483X17301695
Chan SSL, Williamson TJ. Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants. Will Y, Dykens JA, editors. USA: Wiley and Sons; 2017. Detection of Mitochondrial Toxicity using Zebrafish. p323-346.
Majchrzak K, Nelson MH, Bowers JS, Bailey SR, Wyatt MM, Wrangle JM, Rubinstein MP, Varela JC, Li Z, Himes RA, Chan SSL, Paulos CM. β-catenin and PI3Kδ inhibition expands precursor Th17 cells with heightened stemness and antitumor activity. JCI Insight. 2017. 2(8):e90547.
https://insight.jci.org/articles/view/90547
Rahn JJ, Bestman JE, Stackley KD, Chan SSL. Zebrafish lacking functional DNA polymerase gamma survive to juvenile stage, despite rapid and sustained mitochondrial DNA depletion, altered energetics and growth. 2015. Nucleic Acids Research. 43 (21): 10338-10352.
http://nar.oxfordjournals.org/content/43/21/10338.full
Bestman JE, Stackley KD, Rahn JJ, Williamson TJ, Chan SSL. The cellular and molecular progression of mitochondrial dysfunction induced by 2,4-dinitrophenol in developing zebrafish embryos. 2015. Differentiation. 89(3-4):51-69.
http://www.sciencedirect.com/science/article/pii/S0301468115000134
Bohovych I, Chan SSL, Khalimonchuk O. Mitochondrial protein quality control: the mechanisms guarding mitochondrial health. Antioxidants and Redox Signaling. 2015. 22(12):977-94.
http://online.liebertpub.com/doi/abs/10.1089/ars.2014.6199
Jayasundara N, Kozal JS, Arnold MC, Chan SSL, Di Giulio RT. High-throughput tissue bioenergetics analysis reveals equivalent metabolic allometric scaling for teleost hearts and whole organisms. 2015. PLoS ONE. 10(9): e0137710.
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137710
Whitaker RM, Stallons LJ, Kneff JE, Harmon JL, Rahn JJ, Arthur JM, Beeson CC, Chan SSL and Schnellmann RG. Urinary mitochondrial DNA predicts progression of renal dysfunction and mitochondrial disruption in acute kidney injury. Kidney International. 2015. 88(6):1336-1344.
http://www.sciencedirect.com/science/article/pii/S0085253815610481
Bohovych I, Fernandez MR, Rahn JJ, Stackley KD, Bestman JE, Anandhan A, Franco R, Claypool SM, Lewis RE, Chan SSL, Khalimonchuk O. Metalloprotease OMA1 is Involved in Fine-tuning of Mitochondrial Bioenergetic Function and Respiratory Supercomplex Stability. 2015. Scientific Reports. 5:13989.
http://www.nature.com/articles/srep13989
Rahn JJ, Bestman JE, Josey BJ, Inks ES, Stackley KD, Rogers CE, Chou CJ*, Chan SSL*. Novel Vitamin K analogues suppress seizures in zebrafish and mouse models of epilepsy. 2014. Neuroscience. 259: 142-154.
http://www.sciencedirect.com/science/article/pii/S0306452213009871
Ghosh A, Trivedi PP, Timbalia, SA, Griffin AT, Rahn JJ, Chan SSL, Gohil VM. Copper supplementation restores cytochrome c oxidase assembly defect in a mitochondrial disease model of COA6 deficiency. 2014. Human Molecular Genetics, 23(13):3596-3606.
http://hmg.oxfordjournals.org/content/23/13/3596
Rahn JJ, Stackley KD, Chan SSL. Opa1 is required for proper mitochondrial metabolism in early development. 2013. PLoS ONE, 8(3):e59218. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0059218
Stackley KD, Beeson CC, Rahn JJ, Chan SSL. Bioenergetic profiling of zebrafish embryonic development. 2011. PLoS ONE, 6(9): e25652. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0025652
Zhang L*, Chan SSL*, Wolff D. Mitochondrial Disorders of DNA Polymerase Gamma Dysfunction: From Anatomic to Molecular Pathology Diagnosis. 2011. Archives of Pathology and Laboratory Medicine. 135(7):925-34. PMC3158670. * co-first authors http://www.ncbi.nlm.nih.gov/pubmed/21732785
Summary of research prior to joining the Medical University of South Carolina
Oxidative stress and mtDNA mutagenesis in male infertility
Under the mentorship of Dr. Jim Cummins at the Vet. School, Murdoch University we investigated the roles of mitochondrial DNA (mtDNA) mutagenesis and reactive oxygen species (ROS) in male infertility. In collaboration with a major fertility clinic in Western Australia, we measured mitochondrial dysfunction (such as mtDNA mutations, sensitivity to ROS) in spermatazoa from a cohort of infertile men. We found that environmental oxidants could promote the formation of the common mtDNA deletion associated with aging.
New biomarkers for early cartilage degradation in arthritis
Traditionally, radiological measures are used to determine progression of arthritis, but more sensitive methods are needed. For graduate school, I joined the Department of Medicine at the University of Western Australia to work with Drs. Neil Kent, Fiona Lake, and Robert Will at UWA. We developed a number of sensitive assays utilizing new biomarkers of cartilage turnover (Chan et al., Clin Exp Rheumatol, 2001), which were validated against large cohorts of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, twin, exercise, and control populations. Differences in aggrecan processing correlated with disease phenotype, drug treatment, and radiological measures.
Studies of the mtDNA polymerase
For my postdoctoral fellowship, I joined the lab of Dr. Bill Copeland at NIEHS/NIH, whose lab was the first to clone and characterize the human mtDNA polymerase. A diverse range of techniques were utilized to understand mitochondrial dysfunction in disease. As DNA polymerase gamma is the only known DNA polymerase within the mitochondrion, it is absolutely essential for faithful replication, proofreading, and repair of mtDNA. Alpers syndrome is a mtDNA depletion syndrome leading to fatal neurohepatopathy in children. We collaborated with Dr. Robert Naviaux at UCSD, who was the first to link Alpers syndrome with POLG mutations. We screened a cohort of Alpers syndrome patients and found five novel mutations in the catalytic subunit of DNA polymerase gamma (encoded by POLG; Nguyen et al., J Hepatol, 2006). Furthermore, each patient had at least one POLG allele containing either the A467T or W748S mutations, which are the two most common disease mutations in POLG (Chan and Copeland, BBA, 2009). As a result, screening for A467T now constitutes the most rapid and sensitive test for confirming the clinical diagnosis of Alpers syndrome.
Patients with the A467T mutation can develop a range of different mitochondrial diseases. Biochemical characterization of the recombinant A467T protein revealed that the A467T mutation disrupts both normal enzyme catalysis and binding of the catalytic subunit of DNA polymerase gamma to its accessory subunit (Chan et al., J Biol Chem, 2005). We also analyzed fibroblasts from patients carrying the POLG A467T mutation in trans with either a POLG stop codon or intronic frame shift mutation, and showed that transcripts containing the stop codon or frame shift mutation undergo nonsense-mediated decay (Chan et al., DNA Repair, 2005; Chan et al., Mitochondrion, 2009). These events ensured that virtually all POLG protein in the cell derived from the A467T allele, leading to haplotype insufficiency and severe Alpers syndrome.
The second most common POLG mutation, W748S, is generally found in cis with the E1143G polymorphism. It had been a point of contention as to whether polymorphisms participate in the disease process. Using biochemical and structural methods, we showed that the E1143G SNP partially rescues the W748S defect. However, the E1143G SNP renders the protein less stable, thus contributing to mitochondrial dysfunction (Chan et al., Hum Mol Genet, 2006). We have also characterized POLG disease mutations in other regions of the mtDNA polymerase (Kasiviswanathan et al., JBC 2009; Chan and Copeland, Methods Mol Biol, 2009).
A mouse model of mitochondrial toxicity - perinatal exposure to POLG/HIV inhibitors
Pregnant HIV-infected women are often treated with nucleoside reverse transcriptase inhibitors (NRTIs) to prevent vertical transmission of HIV to their children. Unfortunately, these NRTIs also inhibit POLG. In a multi-center study focused on mitochondrial toxicity following perinatal exposure to NRTIs, we showed that AZT-3TC caused persistent mtDNA lesions. Furthermore, this was gender specific, as mtDNA lesions persisted only in female pups after the treatment period (Chan et al., Environ Mol Mutagen, 2007).
A transgenic mouse model of POLG mitochondrial disease
The Y955C mutation in POLG causes autosomal dominant progressive external ophthalmoplegia in humans. We collaborated with Dr. William Lewis (Emory University), whose lab developed a transgenic heart specific Y955C POLG mouse model. These transgenic mice showed mtDNA depletion, increased oxidative stress, cardiomyopathy and reduced lifespan (Lewis et al., Lab Invest, 2007). This is the first mouse model using a known disease mutation in POLG, and pathophysiologically links mtDNA depletion and oxidative stress to defects in POLG.
