title: HIV-1 Vpr disrupts mitochondria axonal transport and accelerates neuronal aging.
abstract: Disruption of mitochondria axonal transport, essential for the maintenance of synaptic and neuronal integrity and function, has been identified in neurodegenerative diseases. Whether HIV-1 viral proteins affect mitochondria axonal transport is unknown, albeit HIV-associated neurocognitive disorders occur in around half of the patients living with HIV. Therefore, we sought to examine the effect of HIV-1 viral protein R (Vpr) on mitochondria axonal transport. Using mice primary neuronal cultures, we demonstrated that 4-day Vpr treatment reduced the ratio of moving mitochondria associated with (i) less energy (ATP) supply, (ii) reduction in Miro-1 and (iii) increase of α-synuclein which led to loss of microtubule stability as demonstrated by inconsecutive distribution of acetylated α-tubulin along the axons. Interestingly, the effect of Vpr on mitochondria axonal transport was partially restored in the presence of bongkrekic acid, a compound that negatively affected the Vpr-adenine nucleotide translocator (ANT) interaction and totally restored the ATP level in neurons. This indicated Vpr impaired mitochondria axonal transport partially related to its interaction with ANT. The above effect of Vpr was similar to the data obtained from hippocampal tissues isolated from 18-month-old aging mice compared to 5-month-old mice. In accord with previous clinical findings that HIV infection prematurely ages the brain and increases the susceptibility to HAND, we found that Vpr induced aging markers in neurons. Thus, we concluded that instead of causing cell death, low concentration of HIV-1 Vpr altered neuronal function related with inhibition of mitochondria axonal transport which might contribute to the accelerated neuronal aging.
authors.affiliation: Molecular Studies of Neurodegenerative Diseases Lab, United States; Department of Neurology, The Fels Institute for Cancer Research & Molecular Biology, United States. Electronic address: wangying8305@gmail.com.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Molecular Studies of Neurodegenerative Diseases Lab, United States; Department of Neurology, The Fels Institute for Cancer Research & Molecular Biology, United States.
authors.forename: Maryline
authors.initials: M
authors.lastname: Santerre
authors.affiliation: Department of Neurology, The Fels Institute for Cancer Research & Molecular Biology, United States.
authors.forename: Italo
authors.initials: I
authors.lastname: Tempera
authors.affiliation: Department of Neurology, The Fels Institute for Cancer Research & Molecular Biology, United States.
authors.forename: Kayla
authors.initials: K
authors.lastname: Martin
authors.affiliation: Molecular Studies of Neurodegenerative Diseases Lab, United States; Department of Neurology, The Fels Institute for Cancer Research & Molecular Biology, United States.
authors.forename: Ruma
authors.initials: R
authors.lastname: Mukerjee
authors.affiliation: Molecular Studies of Neurodegenerative Diseases Lab, United States; Department of Neurology, The Fels Institute for Cancer Research & Molecular Biology, United States; Temple University School of Medicine, Philadelphia, PA 19140, United States. Electronic address: sawaya@temple.edu.
authors.forename: Bassel E
authors.initials: BE
authors.lastname: Sawaya
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D001865:Bongkrekic Acid / Q000494:pharmacology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D015497:HIV-1; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D006801:Humans; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D018696:Neuroprotective Agents / Q000494:pharmacology; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051844:alpha-Synuclein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: C573782:Miro-1 protein, mouse; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051844:alpha-Synuclein; D054325:vpr Gene Products, Human Immunodeficiency Virus; D001865:Bongkrekic Acid; D000255:Adenosine Triphosphate; D020741:rho GTP-Binding Proteins
keywords: Aging; HIV-Associated neurocognitive disorder; Mitochondria axonal transport; Viral protein R; α-synuclein