TY - JOUR
T1 - Methamphetamine augments concurrent astrocyte mitochondrial stress, oxidative burden, and antioxidant capacity
T2 - Tipping the balance in HIV-associated neurodegeneration
AU - Borgmann, Kathleen
AU - Ghorpade, Anuja
N1 - Funding Information:
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.
Publisher Copyright:
© Springer Science+Business Media, LLC 2017.
PY - 2018/2
Y1 - 2018/2
N2 - 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.
AB - 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.
KW - Astroglia
KW - Dynamin-related protein
KW - Extracellular flux
KW - Machine learning
KW - Mitochondria
KW - Mitofusin
KW - Neurotoxicity
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85030850049&partnerID=8YFLogxK
U2 - 10.1007/s12640-017-9812-z
DO - 10.1007/s12640-017-9812-z
M3 - Article
C2 - 28993979
AN - SCOPUS:85030850049
SN - 1029-8428
VL - 33
SP - 433
EP - 447
JO - Neurotoxicity Research
JF - Neurotoxicity Research
IS - 2
ER -