Dietary restriction augments protection against induction of the mitochondrial permeability transition

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.