Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences, Sukileliu Av. 13, LT-50162 Kaunas, Lithuania.
Department of Biochemistry, Faculty of Medicine, Lithuanian University of Health Sciences, Eiveniu Str. 4, LT-50161 Kaunas, Lithuania.
Int J Mol Sci. 2024 Jun 5;25(11):6223. doi: 10.3390/ijms25116223.
Renal ischemia/reperfusion is a serious condition that not only causes acute kidney injury, a severe clinical syndrome with high mortality, but is also an inevitable part of kidney transplantation or other kidney surgeries. Alterations of oxygen levels during ischemia/reperfusion, namely hypoxia/reoxygenation, disrupt mitochondrial metabolism and induce structural changes that lead to cell death. A signature mitochondrial phospholipid, cardiolipin, with many vital roles in mitochondrial homeostasis, is one of the key players in hypoxia/reoxygenation-induced mitochondrial damage. In this study, we analyze the effect of hypoxia/reoxygenation on human renal proximal tubule epithelial cell (RPTEC) cardiolipins, as well as their metabolism and mitochondrial functions. RPTEC cells were placed in a hypoxic chamber with a 2% oxygen atmosphere for 24 h to induce hypoxia; then, they were replaced back into regular growth conditions for 24 h of reoxygenation. Surprisingly, after 24 h, hypoxia cardiolipin levels substantially increased and remained higher than control levels after 24 h of reoxygenation. This was explained by significantly elevated levels of cardiolipin synthase and lysocardiolipin acyltransferase 1 (LCLAT1) gene expression and protein levels. Meanwhile, hypoxia/reoxygenation decreased ADP-dependent mitochondrial respiration rates and oxidative phosphorylation capacity and increased reactive oxygen species generation. Our findings suggest that hypoxia/reoxygenation induces cardiolipin remodeling in response to reduced mitochondrial oxidative phosphorylation in a way that protects mitochondrial function.
肾缺血/再灌注是一种严重的情况，不仅会导致急性肾损伤，这是一种死亡率很高的严重临床综合征，而且也是肾移植或其他肾脏手术不可避免的一部分。缺血/再灌注过程中氧水平的改变，即缺氧/再氧合，会破坏线粒体代谢并诱导导致细胞死亡的结构变化。一种标志性的线粒体磷脂，心磷脂，在心磷脂在线粒体稳态中的许多重要作用中，是缺氧/再氧合诱导的线粒体损伤的关键因素之一。在这项研究中，我们分析了缺氧/再氧合对人肾近端小管上皮细胞（RPTEC）心磷脂的影响，以及它们的代谢和线粒体功能。将 RPTEC 细胞置于含 2%氧气的缺氧室中 24 小时以诱导缺氧；然后，将它们替换回常规生长条件下进行 24 小时的再氧合。令人惊讶的是，24 小时后，缺氧下心磷脂水平显著增加，并在再氧合 24 小时后仍保持高于对照水平。这可以通过心磷脂合酶和溶血心磷脂酰基转移酶 1（LCLAT1）基因表达和蛋白水平的显著升高来解释。同时，缺氧/再氧合降低了 ADP 依赖性线粒体呼吸速率和氧化磷酸化能力，并增加了活性氧的产生。我们的研究结果表明，缺氧/再氧合会诱导心磷脂重塑，以适应线粒体氧化磷酸化减少的情况，从而保护线粒体功能。
