HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders.

Abstract

HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of HIV patients, and therapies to combat HAND progression are urgently needed. HIV proteins are released from infected cells and cause neuronal damage, possibly through mitochondrial abnormalities. Altered mitochondrial fission and fusion is implicated in several neurodegenerative disorders. Here, we hypothesized that mitochondrial fission/fusion may be dysregulated in neurons during HAND. We have identified decreased mitochondrial fission protein (dynamin 1-like; DNM1L) in frontal cortex tissues of HAND donors, along with enlarged and elongated mitochondria localized to the soma of damaged neurons. Similar pathology was observed in the brains of GFAP-gp120 tg mice. In vitro, recombinant gp120 decreased total and active DNM1L levels, reduced the level of Mitotracker staining, and increased extracellular acidification rate (ECAR) in primary neurons. DNM1L knockdown enhanced the effects of gp120 as measured by reduced Mitotracker signal in the treated cells. Interestingly, overexpression of DNM1L increased the level of Mitotracker staining in primary rat neurons and reduced neuroinflammation and neurodegeneration in the GFAP-gp120-tg mice. These data suggest that mitochondrial biogenesis dynamics are shifted towards mitochondrial fusion in brains of HAND patients and this may be due to gp120-induced reduction in DNM1L activity. Promoting mitochondrial fission during HIV infection of the CNS may restore mitochondrial biogenesis and prevent neurodegeneration.

• Authors: Jerel Adam Fields, Elisabeth Serger, Sofia Campos, Ajit S Divakaruni, Changyoun Kim, Kendall Smith, Margarita Trejo, Anthony Adame, Brian Spencer, Edward Rockenstein, Anne N Murphy, Ronald J Ellis, Scott Letendre, Igor Grant, Eliezer Masliah
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 86 Pg. 154-69 (02 2016) ISSN: 1095-953X [Electronic] United States
• PMID: 26611103 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• HIV Envelope Protein gp120
• Microtubule-Associated Proteins
• Mitochondrial Membrane Transport Proteins
• Mitochondrial Proteins
• GTP Phosphohydrolases
• Mfn1 protein, human
• DNM1L protein, human
• Dynamins

Topics

• Adult
• Animals
• Brain (metabolism, ultrastructure, virology)
• Cognition Disorders (metabolism, virology)
• Dynamins
• Encephalitis (metabolism, virology)
• Female
• Frontal Lobe (metabolism, ultrastructure, virology)
• GTP Phosphohydrolases (metabolism)
• HIV Envelope Protein gp120 (metabolism)
• HIV Infections (complications)
• Humans
• Male
• Mice
• Microtubule-Associated Proteins (metabolism)
• Middle Aged
• Mitochondria (metabolism, ultrastructure, virology)
• Mitochondrial Dynamics
• Mitochondrial Membrane Transport Proteins (metabolism)
• Mitochondrial Proteins (metabolism)
• Neurons (metabolism, ultrastructure, virology)
• Rats
• Rats, Sprague-Dawley
• Tumor Cells, Cultured