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Mitochondrial dysfunction in human immunodeficiency virus-1 transgenic mouse cardiac myocytes #MMPMID30256393
Cheung JY; Gordon J; Wang J; Song J; Zhang XQ; Prado FJ; Shanmughapriya S; Rajan S; Tomar D; Tahrir FG; Gupta MK; Knezevic T; Merabova N; Kontos CD; McClung JM; Klotman PE; Madesh M; Khalili K; Feldman AM
J Cell Physiol 2019[Apr]; 234 (4): 4432-4444 PMID30256393show ga
The pathophysiology of human immunodeficiency virus (HIV)-associated cardiomyopathy remains uncertain. We used HIV-1 transgenic (Tg26) mice to explore mechanisms by which HIV-related proteins impacted on myocyte function. Compared to adult ventricular myocytes isolated from nontransgenic (wild type [WT]) littermates, Tg26 myocytes had similar mitochondrial membrane potential (DeltaPsi (m) ) under normoxic conditions but lower Delta Psi (m) after hypoxia/reoxygenation (H/R). In addition, Delta Psi (m) in Tg26 myocytes failed to recover after Ca (2+) challenge. Functionally, mitochondrial Ca (2+) uptake was severely impaired in Tg26 myocytes. Basal and maximal oxygen consumption rates (OCR) were lower in normoxic Tg26 myocytes, and further reduced after H/R. Complex I subunit and ATP levels were lower in Tg26 hearts. Post-H/R, mitochondrial superoxide (O (2)(*-) ) levels were higher in Tg26 compared to WT myocytes. Overexpression of B-cell lymphoma 2-associated athanogene 3 (BAG3) reduced O (2)(*-) levels in hypoxic WT and Tg26 myocytes back to normal. Under normoxic conditions, single myocyte contraction dynamics were similar between WT and Tg26 myocytes. Post-H/R and in the presence of isoproterenol, myocyte contraction amplitudes were lower in Tg26 myocytes. BAG3 overexpression restored Tg26 myocyte contraction amplitudes to those measured in WT myocytes post-H/R. Coimmunoprecipitation experiments demonstrated physical association of BAG3 and the HIV protein Tat. We conclude: (a) Under basal conditions, mitochondrial Ca (2+) uptake, OCR, and ATP levels were lower in Tg26 myocytes; (b) post-H/R, Delta Psi (m) was lower, mitochondrial O (2)(*-) levels were higher, and contraction amplitudes were reduced in Tg26 myocytes; and (c) BAG3 overexpression decreased O (2)(*-) levels and restored contraction amplitudes to normal in Tg26 myocytes post-H/R in the presence of isoproterenol.
|*Energy Metabolism[MESH]
|Adaptor Proteins, Signal Transducing/genetics/metabolism[MESH]
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J+Cell+Physiol 2019 ; 234 (4): 4432-4444
