Leontieva Olga V, Blagosklonny Mikhail V
Cell Stress Biology; Roswell Park Cancer Institute; Buffalo, NY USA.
Cell Cycle. 2014;13(4):509-15. doi: 10.4161/cc.27973. Epub 2014 Jan 23.
A groundbreaking publication by Sinclair and coworkers has illuminated the pseudo-hypoxic state in aging and its reversibility. Remarkably, these data also fit the mTOR-centered model of aging. Here we discuss that the mTOR pathway can cause cellular pseudo-hypoxic state, manifested by HIF-1 expression and lactate production under normoxia. We found that rapamycin decreased HIF-1 and lactate levels in proliferating and senescent cells in vitro. This reduction was independent from mitochondrial respiration: rapamycin decreased lactate production in normoxia, hypoxia, and in the presence of the OXPHOS inhibitor oligomycin. We suggest that pseudo-hypoxic state is not necessarily caused by mitochondrial dysfunction, but instead mitochondrial dysfunction may be secondary to mTOR-driven hyperfunctions. Clinical applications of rapamycin for reversing pseudo-hypoxic state and lactate acidosis are discussed.
辛克莱及其同事发表的一篇开创性论文揭示了衰老过程中的假性缺氧状态及其可逆性。值得注意的是，这些数据也符合以mTOR为中心的衰老模型。在此我们讨论mTOR信号通路可导致细胞假性缺氧状态，在常氧条件下表现为HIF-1表达和乳酸生成。我们发现雷帕霉素可降低体外增殖细胞和衰老细胞中的HIF-1和乳酸水平。这种降低与线粒体呼吸无关：雷帕霉素在常氧、缺氧及存在氧化磷酸化抑制剂寡霉素的情况下均可降低乳酸生成。我们认为假性缺氧状态不一定由线粒体功能障碍引起，相反，线粒体功能障碍可能继发于mTOR驱动的功能亢进。文中还讨论了雷帕霉素在逆转假性缺氧状态和乳酸性酸中毒方面的临床应用。
