Kristal B S, Yu B P
Department of Physiology, University of Texas Health Science Center, San Antonio, USA.
Free Radic Biol Med. 1998 May;24(7-8):1269-77. doi: 10.1016/s0891-5849(97)00444-9.
Exposure to oxidants or phosphate, especially in the presence of calcium, has been long known to lead to mitochondrial structural alteration and damage. In the past 15 years, it has become increasingly appreciated that this damage is often the result of a cyclosporin A-sensitive event, the "permeability transition" (PT). Using liver mitochondria isolated from male Fischer 344 rats of 6-24 months of age, we now present evidence that long-term, life-prolonging, dietary restriction regimens greatly delay induction of a PT following challenge. Dietary restriction slowed induction by 25 microM calcium, or by calcium in conjunction with the strong oxidant t-butyl hydroperoxide, by approximately 50%. The increased resistance to PT induction was maintained through 24 months of age. Dietary restriction also protected against t-butyl hydroperoxide in the presence of high calcium challenges (250 microM), although the extent of this protection was age-dependent. Induction by 2.5 mM phosphate alone was blocked in most 6-month-old dietary restricted animals and was slowed by 50-100% in animals 12-24 months of age. Susceptibility to 25 microM calcium in conjunction with phosphate varied in an age-dependent manner, ranging from 4-12 times slower in the dietary restricted animals than in their ad lib fed counterparts. Together, these data provide evidence that the factors regulating PT induction are affected by long-term physiological and environmental conditions such as age and diet. The observed effects represent one of the largest recognized dietary restriction-mediated increases in a parameter related to antioxidant defenses. These data also suggest that the endogenous defense systems that protect mitochondria from calcium in conjunction with inorganic phosphate differ from those that protect against calcium in conjunction with an oxidant.
长期以来，人们都知道暴露于氧化剂或磷酸盐中，尤其是在有钙存在的情况下，会导致线粒体结构改变和损伤。在过去的15年里，人们越来越认识到这种损伤通常是由环孢菌素A敏感事件，即“通透性转换”（PT）引起的。我们使用从6至24月龄雄性Fischer 344大鼠分离的肝线粒体，现在提供证据表明，长期的、延长寿命的饮食限制方案能极大地延迟应激后PT的诱导。饮食限制使25微摩尔钙或钙与强氧化剂叔丁基过氧化氢联合作用诱导PT的时间延缓了约50%。对PT诱导的抗性增加在24月龄时仍得以维持。在高钙应激（250微摩尔）存在的情况下，饮食限制也能保护线粒体免受叔丁基过氧化氢的损伤，尽管这种保护程度与年龄有关。在大多数6月龄饮食限制的动物中，单独2.5毫摩尔磷酸盐诱导的PT被阻断，在12至24月龄的动物中诱导速度减慢了50 - 100%。对25微摩尔钙与磷酸盐联合作用的敏感性随年龄而变化，饮食限制的动物比自由采食的对照动物慢4至12倍。总之，这些数据提供了证据，表明调节PT诱导的因素受年龄和饮食等长期生理和环境条件的影响。观察到的效应代表了饮食限制介导的与抗氧化防御相关参数增加中最大的已知效应之一。这些数据还表明，保护线粒体免受钙与无机磷酸盐联合作用影响的内源性防御系统不同于保护线粒体免受钙与氧化剂联合作用影响的防御系统。
