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Title: Multimodal LA-ICP-MS and nanoSIMS imaging enables copper mapping within photoreceptor megamitochondria in a zebrafish model of Menkes disease

Abstract

Here, copper is essential for eukaryotic life, and animals must acquire this nutrient through the diet and distribute it to cells and organelles for proper function of biological targets. Indeed, mutations in the central copper exporter ATP7A contribute to a spectrum of diseases, including Menkes disease, with symptoms ranging from neurodegeneration to lax connective tissue. As such, a better understanding of the fundamental impacts of ATP7A mutations on in vivo copper distributions is of relevance to those affected by these diseases. For this work, we combine metal imaging and optical imaging techniques at a variety of spatial resolutions to identify tissues and structures with altered copper levels in the Calamitygw71 zebrafish model of Menkes disease. Rapid profiling of tissue slices with LA-ICP-MS identified reduced copper levels in the brain, neuroretina, and liver of Menkes fish compared to control specimens. High resolution nanoSIMS imaging of the neuroretina, combined with electron and confocal microscopies, identified the megamitochondria of photoreceptors as loci of copper accumulation in wildtype fish, with lower levels of megamitochondrial copper observed in Calamitygw71 zebrafish. Interestingly, this localized copper decrease does not result in impaired photoreceptor development or altered megamitochondrial morphology, suggesting the prioritization of copper at sufficient levels formore » maintaining essential mitochondrial functions. Together, these data establish the Calamitygw71 zebrafish as an optically transparent in vivo model for the study of neural copper misregulation, illuminate a role for the ATP7A copper exporter in trafficking copper to the neuroretina, and highlight the utility of combining multiple imaging techniques for studying metals in whole organism settings with spatial resolution.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [2];  [3]
  1. Univ. of California, Berkeley, CA (United States)
  2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
  3. Univ. of California, Berkeley, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE National Nuclear Security Administration (NNSA); USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23). Biological Systems Science Division; National Institutes of Health (NIH); Fannie and John Hertz Foundation; Canadian Inst. for Advanced Research (CIFAR)
OSTI Identifier:
1467817
Report Number(s):
LLNL-JRNL-745593
Journal ID: ISSN 1756-5901; METAIR; 930110
Grant/Contract Number:  
AC52-07NA27344; GM 79465; T32 GM066698; SCW1039
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Metallomics
Additional Journal Information:
Journal Volume: 10; Journal Issue: 3; Journal ID: ISSN 1756-5901
Publisher:
Royal Society of Chemistry
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Ackerman, Cheri M., Weber, Peter K., Xiao, Tong, Thai, Bao, Kuo, Tiffani J., Zhang, Emily, Pett-Ridge, Jennifer, and Chang, Christopher J.. Multimodal LA-ICP-MS and nanoSIMS imaging enables copper mapping within photoreceptor megamitochondria in a zebrafish model of Menkes disease. United States: N. p., 2018. Web. doi:10.1039/c7mt00349h.
Ackerman, Cheri M., Weber, Peter K., Xiao, Tong, Thai, Bao, Kuo, Tiffani J., Zhang, Emily, Pett-Ridge, Jennifer, & Chang, Christopher J.. Multimodal LA-ICP-MS and nanoSIMS imaging enables copper mapping within photoreceptor megamitochondria in a zebrafish model of Menkes disease. United States. doi:10.1039/c7mt00349h.
Ackerman, Cheri M., Weber, Peter K., Xiao, Tong, Thai, Bao, Kuo, Tiffani J., Zhang, Emily, Pett-Ridge, Jennifer, and Chang, Christopher J.. Tue . "Multimodal LA-ICP-MS and nanoSIMS imaging enables copper mapping within photoreceptor megamitochondria in a zebrafish model of Menkes disease". United States. doi:10.1039/c7mt00349h.
@article{osti_1467817,
title = {Multimodal LA-ICP-MS and nanoSIMS imaging enables copper mapping within photoreceptor megamitochondria in a zebrafish model of Menkes disease},
author = {Ackerman, Cheri M. and Weber, Peter K. and Xiao, Tong and Thai, Bao and Kuo, Tiffani J. and Zhang, Emily and Pett-Ridge, Jennifer and Chang, Christopher J.},
abstractNote = {Here, copper is essential for eukaryotic life, and animals must acquire this nutrient through the diet and distribute it to cells and organelles for proper function of biological targets. Indeed, mutations in the central copper exporter ATP7A contribute to a spectrum of diseases, including Menkes disease, with symptoms ranging from neurodegeneration to lax connective tissue. As such, a better understanding of the fundamental impacts of ATP7A mutations on in vivo copper distributions is of relevance to those affected by these diseases. For this work, we combine metal imaging and optical imaging techniques at a variety of spatial resolutions to identify tissues and structures with altered copper levels in the Calamitygw71 zebrafish model of Menkes disease. Rapid profiling of tissue slices with LA-ICP-MS identified reduced copper levels in the brain, neuroretina, and liver of Menkes fish compared to control specimens. High resolution nanoSIMS imaging of the neuroretina, combined with electron and confocal microscopies, identified the megamitochondria of photoreceptors as loci of copper accumulation in wildtype fish, with lower levels of megamitochondrial copper observed in Calamitygw71 zebrafish. Interestingly, this localized copper decrease does not result in impaired photoreceptor development or altered megamitochondrial morphology, suggesting the prioritization of copper at sufficient levels for maintaining essential mitochondrial functions. Together, these data establish the Calamitygw71 zebrafish as an optically transparent in vivo model for the study of neural copper misregulation, illuminate a role for the ATP7A copper exporter in trafficking copper to the neuroretina, and highlight the utility of combining multiple imaging techniques for studying metals in whole organism settings with spatial resolution.},
doi = {10.1039/c7mt00349h},
journal = {Metallomics},
number = 3,
volume = 10,
place = {United States},
year = {Tue Mar 06 00:00:00 EST 2018},
month = {Tue Mar 06 00:00:00 EST 2018}
}

Journal Article:
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