Abstract
Methamphetamine (METH) use, with and without human immunodeficiency virus (HIV)-1 comorbidity, exacerbates neurocognitive decline. Oxidative stress is a probable neurotoxic mechanism during HIV-1 central nervous system infection and METH abuse, as viral proteins, antiretroviral therapy and METH have each been shown to induce mitochondrial dysfunction. However, the mechanisms regulating mitochondrial homeostasis and overall oxidative burden in astrocytes are not well understood in the context of HIV-1 infection and METH abuse. Here, we report METH-mediated dysregulation of astrocyte mitochondrial morphology and function during prolonged exposure to low levels of METH. Mitochondria became larger and more rod shaped with METH when assessed by machine learning, segmentation analyses. These changes may be mediated by elevated mitofusin expression coupled with inhibitory phosphorylation of dynamin-related protein-1, which regulate mitochondrial fusion and fission, respectively. While METH decreased oxygen consumption and ATP levels during acute exposure, chronic treatment of 1 to 2 weeks significantly enhanced both when tested in the absence of METH. Together, these changes significantly increased not only expression of antioxidant proteins, augmenting the astrocyte’s oxidative capacity, but also oxidative damage. We propose that targeting astrocytes to reduce their overall oxidative burden and expand their antioxidant capacity could ultimately tip the balance from neurotoxicity towards neuroprotection.
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Acknowledgements
The authors appreciate Lin Tang and Satomi Stacy for providing consistent high-quality primary astrocyte cultures and Dr. Richa Pandey, Dr. Brian Molles, Dr. Shruthi Nooka, Chaitanya Joshi, Venkata Viswanadh Edara, and Shannon Mythen for critical reading of the manuscript. Special additional thanks to Ms. Stacy and Lenore Price for technical and editing assistance, Dr. Irma E. Cisneros for the mPTP experimental images, and Dr. Sebastian Requena for assistance with Weka segmentation. This study was funded by the National Institute of Drug Abuse (R01 DA039789) to AG. KB was supported by a NINDS T32 AG020494 Neurobiology of Aging Associate Fellowship. We appreciate the assistance of the Laboratory of Developmental Biology for providing human brain tissues, supported by NIH 5R24 HD0008836 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development.
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Supplementary Fig. 1
Mitochondria segmention into morphological types with Weka machine learning in Fiji, ImageJ. Human astrocytes were exposed to 0 nM, 50 nM, 5 μM, or 500 μM METH for 1 week. Mitochondria were then fluorescently labeled with Mitotracker Red® (MTR)(a). Mitochondrial morphology was assessed using Fiji ImageJ software; Version: 2.0.0-rc-41/1.5d and machine learning “Trainable Weka Segmentation” (version 3.211, Weka V3.9.0) as developed by Arganda-Carreras et al. (2017). The Weka was trained based on mitochondrial morphology (punctate, rod-shaped, large-spots and networked mitochondria) as previously described (Collins et al. 2002; Dagda et al. 2009; Wang et al. 2008; Yu et al. 2006). The probability image stack was then separated into five individual layers: punctate (b), rod-shaped (b), large-spots (c), networks (e), and background (f). The area and fold change in average size in each morphology were calculated from 10 to 15 micrographs per condition. Each layer was inverted to show mitochondria-specific fluorescence as black pixels, and then the threshold was adjusted to optimally resolve individual mitochondria. The process “analyze particles” was used on each image and the number of particles, size of particles, and percent image area was recorded. (GIF 387 kb)
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Borgmann, K., Ghorpade, A. Methamphetamine Augments Concurrent Astrocyte Mitochondrial Stress, Oxidative Burden, and Antioxidant Capacity: Tipping the Balance in HIV-Associated Neurodegeneration. Neurotox Res 33, 433–447 (2018). https://doi.org/10.1007/s12640-017-9812-z
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DOI: https://doi.org/10.1007/s12640-017-9812-z