title: HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution.
abstract: With the advent of the combination antiretroviral therapy era (cART), the development of AIDS has been largely limited in the USA. Unfortunately, despite the development of efficacious treatments, HIV-1-associated neurocognitive disorders (HAND) can still develop, and as many HIV-1 positive individuals age, the prevalence of HAND is likely to rise because HAND manifests in the brain with very low levels of virus. However, the mechanism producing this viral disorder is still debated. Interestingly, HIV-1 infection exposes neurons to proteins including Tat, Nef, and Vpr which can drastically alter mitochondrial properties. Mitochondrial dysfunction has been posited to be a cornerstone of the development of numerous neurodegenerative diseases. Therefore, we investigated mitochondria in an animal model of HAND. Using an HIV-1 transgenic rat model expressing seven of the nine HIV-1 viral proteins, mitochondrial functional and proteomic analysis were performed on a subset of mitochondria that are particularly sensitive to cellular changes, the neuronal synaptic mitochondria. Quantitative mass spectroscopic studies followed by statistical analysis revealed extensive proteome alteration in this model paralleling mitochondrial abnormalities identified in HIV-1 animal models and HIV-1-infected humans. Novel mitochondrial protein changes were discovered in the electron transport chain (ETC), the glycolytic pathways, mitochondrial trafficking proteins, and proteins involved in various energy pathways, and these findings correlated well with the function of the mitochondria as assessed by a mitochondrial coupling and flux assay. By targeting these proteins and proteins upstream in the same pathway, we may be able to limit the development of HAND.
authors: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA.
authors: Lance M
authors: LM
authors: Villeneuve
authors: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA.
authors: Phillip R
authors: PR
authors: Purnell
authors: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA.
authors: Kelly L
authors: KL
authors: Stauch
authors: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA.
authors: Shannon E
authors: SE
authors: Callen
authors: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA.
authors: Shilpa J
authors: SJ
authors: Buch
authors: Departments of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985800 Nebraska Medical Center-DRC1 3008, Omaha, NE, 68198-5800, USA. hfox@unmc.edu.
authors: Howard S
authors: HS
authors: Fox
mesh_terms: D015526:AIDS Dementia Complex / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000235:genetics; D015497:HIV-1 / Q000737:chemistry* / Q000472:pathogenicity / Q000502:physiology; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D045222:Electron Transport Chain Complex Proteins; D024101:Mitochondrial Proteins; D020543:Proteome
keywords: HIV-1-associated neurocognitive disorders; Mitochondria; Neurodegeneration; neuroAIDS