Minocycline protects against the mitochondria permeability transition after both warm and cold ischemia-reperfusion

Zhang, Xun; Schwartz, Justin; Ramshesh, Venkat K.; Pediaditakis, Peter; Holmuhamedov, Ekhson; Zhong, Zhi; Theruvath, Tom P.; Lemasters, John J.

doi:10.1002/hep.23453

Cited by 1 publication

(1 citation statement)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Minocycline, but not tetracycline, inhibits the MPT and prevents cell killing after both warm and cold I/R (Theruvath et al 2008b; Zhang et al 2010). To test the hypothesis that cytoprotection by tetracycline derivatives was related to inhibition of the MPT, we assessed the panel of tetracycline derivatives for their ability to block the MPT in isolated mitochondria.…”

Section: Resultsmentioning

confidence: 99%

Minocycline and doxycycline, but not other tetracycline-derived compounds, protect liver cells from chemical hypoxia and ischemia/reperfusion injury by inhibition of the mitochondrial calcium uniporter

Schwartz

Holmuhamedov

Zhang

et al. 2013

Toxicology and Applied Pharmacology

Self Cite

View full text Add to dashboard Cite

Minocycline, a tetracycline-derived compound, mitigates damage caused by ischemia/reperfusion (I/R) injury. Here, 19 tetracycline-derived compounds were screened in comparison to minocycline for their ability to protect hepatocytes against damage from chemical hypoxia and I/R injury. Cultured rat hepatocytes were incubated with 50 μM of each tetracycline-derived compound 20 min prior to exposure to 500 μM iodoacetic acid plus 1 mM KCN (chemical hypoxia). In other experiments, hepatocytes were incubated in anoxic Krebs-Ringer-Hepes buffer (KRH) at pH 6.2 for 4 h prior to reoxygenation at pH 7.4 (simulated I/R). Tetracycline-derived compounds were added 20 min prior to reperfusion. Ca2+ uptake was measured in isolated rat liver mitochondria incubated with Fluo-5N. Cell killing after 120 min of chemical hypoxia measured by propidium iodide (PI) fluorometery was 87%, which decreased to 28% and 42% with minocycline and doxycycline, respectively. After I/R, cell killing at 120 min decreased from 79% with vehicle to 43% and 49% with minocycline and doxycycline. No other tested compound decreased killing. Minocycline and doxycycline also inhibited mitochondrial Ca2+ uptake and suppressed the Ca2+-induced mitochondrial permeability transition (MPT), the penultimate cause of cell death in reperfusion injury. Ru360, a specific inhibitor of the mitochondrial calcium uniporter (MCU), also decreased cell killing after hypoxia and I/R and blocked mitochondrial Ca2+ uptake and the MPT. Other proposed mechanisms, including mitochondrial depolarization and matrix metalloprotease inhibition could not account for cytoprotection. Taken together, these results indicate that minocycline and doxycycline are cytoprotective by way of inhibition of MCU.

show abstract

Section: Resultsmentioning

confidence: 99%