HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders.
Title | HIV alters neuronal mitochondrial fission/fusion in the brain during HIV-associated neurocognitive disorders. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Fields, JAdam, Serger, E, Campos, S, Divakaruni, AS, Kim, C, Smith, K, Trejo, M, Adame, A, Spencer, B, Rockenstein, E, Murphy, AN, Ellis, RJ, Letendre, S, Grant, I, Masliah, E |
Journal | Neurobiol Dis |
Volume | 86 |
Pagination | 154-69 |
Date Published | 2016 Feb |
ISSN | 1095-953X |
Keywords | Adult, Animals, Brain, Cognition Disorders, Dynamins, Encephalitis, Female, Frontal Lobe, GTP Phosphohydrolases, HIV Envelope Protein gp120, HIV Infections, Humans, Male, Mice, Microtubule-Associated Proteins, Middle Aged, Mitochondria, Mitochondrial Dynamics, Mitochondrial Membrane Transport Proteins, Mitochondrial Proteins, Neurons, Rats, Rats, Sprague-Dawley, Tumor Cells, Cultured |
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. |
DOI | 10.1016/j.nbd.2015.11.015 |
Alternate Journal | Neurobiol Dis |
PubMed ID | 26611103 |
PubMed Central ID | PMC4713337 |
Grant List | K24 MH097673 / MH / NIMH NIH HHS / United States P50 AG005131 / AG / NIA NIH HHS / United States R01 AG043384 / AG / NIA NIH HHS / United States MH062962 / MH / NIMH NIH HHS / United States R01 NS087611 / NS / NINDS NIH HHS / United States U24 MH100928 / MH / NIMH NIH HHS / United States MH5974 / MH / NIMH NIH HHS / United States P30 NS076411 / NS / NINDS NIH HHS / United States 1F32NS083426-01 / NS / NINDS NIH HHS / United States R01 MH062962 / MH / NIMH NIH HHS / United States F32 NS083426 / NS / NINDS NIH HHS / United States R37 AG018440 / AG / NIA NIH HHS / United States P30 MH062512 / MH / NIMH NIH HHS / United States AG043384 / AG / NIA NIH HHS / United States NS087611 / NS / NINDS NIH HHS / United States MH100928 / MH / NIMH NIH HHS / United States |