Astrocytic metabolic switch is a novel etiology for Cocaine and HIV-1 Tat-mediated neurotoxicity article

Kalimuthusamy Natarajaseenivasan, Bianca Cotto, Santhanam Shanmughapriya, Alyssa A. Lombardi, Prasun K. Datta, Muniswamy Madesh, John W. Elrod, Kamel Khalili, Dianne Langford

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13 Scopus citations

Abstract

Calcium (Ca2+) dynamics and oxidative signaling control mitochondrial bioenergetics in the central nervous system, where astrocytes are a major energy source for neurons. Cocaine use exacerbates HIV-associated neurocognitive disorders, but little is known about disruptions in astrocyte metabolism in this context. Our data show that the HIV protein Tat and cocaine induce a metabolic switch from glucose to fatty acid oxidation in astrocytes, thereby limiting lactate transport to neurons. Mechanistic analyses revealed increased Mitochondrial Ca2+ Uniporter (MCU)-mediated Ca2+ uptake in astrocytes exposed to Tat and cocaine due to oxidation of MCU. Since our data suggest that mitochondrial oxidation is dependent in part on MCU-mediated Ca2+ uptake, we targeted MCU to restore glycolysis in astrocytes to normalize extracellular lactate levels. Knocking down MCU in astrocytes prior to Tat and cocaine exposure prevented metabolic switching and protected neurons. These findings identify a novel molecular mechanism underlying neuropathogenesis in HIV and cocaine use.

Original languageEnglish (US)
Article number415
JournalCell Death and Disease
Volume9
Issue number4
DOIs
StatePublished - Jan 1 2018

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

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    Natarajaseenivasan, K., Cotto, B., Shanmughapriya, S., Lombardi, A. A., Datta, P. K., Madesh, M., Elrod, J. W., Khalili, K., & Langford, D. (2018). Astrocytic metabolic switch is a novel etiology for Cocaine and HIV-1 Tat-mediated neurotoxicity article. Cell Death and Disease, 9(4), [415]. https://doi.org/10.1038/s41419-018-0422-3