Abstract:
:Lon protease, an ATP dependent mitochondrial protease, is important in mitochondrial protein maintenance. Disruption of protein homeostasis and mitochondrial dysfunction is associated with lipodystrophy, metabolic syndrome and accelerated aging, and are commonly observed in patients on long term antiretroviral therapy. Sirtuin 3 (SIRT3) is a post-translational regulator of Lon and regulates antioxidant response. We previously showed the nucleoside analogues (NRTIs), Zidovudine (AZT; 7.1 μM), Stavudine (d4T; 4 μM), and Tenofovir (TFV; 1.2 μM) induced oxidative stress and mitochondrial dysfunction in human hepatoma (HepG2) cells at 24 h (h) and 120 h. We conducted a mitochondrial proteomic assessment of homeostasis in the same model, using the same NRTIs. Protein expression of Lon, SIRT3, heat shock protein (HSP) 60, phospho-eukaryotic translation initiation factor 2α (p-eIF2α; Ser51) and phospho-c-jun N-terminal kinase (p-JNK; Thr183/Tyr185) were quantified by western blots. The data showed all stress responses were significantly increased in HepG2 cells by all antiretroviral drugs at 24 h (p < 0.0001); however, at 120 h, a significant depletion in the ATP-dependent proteins Lon (p = 0.00013) and HSP60 (p < 0.0001) was observed. Proteins initiated by endoplasmic reticulum stress: p-eIF2α (p = 0.001) and p-JNK (p = 0.0029), were significantly reduced following prolonged treatment. SIRT3 was maintained at elevated levels in the treated cells following prolonged exposure (p < 0.001). We conclude that the ATP dependent proteins are more relevant to acute toxicity, while SIRT3 confers protection over prolonged periods of toxicity.
journal_name
Chem Biol Interactjournal_title
Chemico-biological interactionsauthors
Nagiah S,Phulukdaree A,Chuturgoon AAdoi
10.1016/j.cbi.2016.03.021subject
Has Abstractpub_date
2016-05-25 00:00:00pages
82-6eissn
0009-2797issn
1872-7786pii
S0009-2797(16)30091-6journal_volume
252pub_type
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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journal_title:Chemico-biological interactions
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abstract::Oxidative stress and oxidative damage to tissues are common end points of chronic diseases such as atherosclerosis, diabetes, and rheumatoid arthritis. Oxidative stress in diabetes coexists with a reduction in the antioxidant status, which can further increase the deleterious effects of free radicals. The aim of the p...
journal_title:Chemico-biological interactions
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abstract:BACKGROUND:Head and neck squamous cell carcinoma (HNSCC) is one of the most common lethal tumors with a high recurrence rate and low survival rate. Therefore, an urgent need exists for novel and effective treatment strategies for HNSCC patients. METHODS:Osthole, a natural ingredient extracted from Cnidium monnieri (L....
journal_title:Chemico-biological interactions
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