Regulation of kidney mitochondrial function by caloric restriction

Caloric restriction (CR) prevents obesity and increases resilience against pathological stimuli in laboratory rodents. At the mitochondrial level, protection promoted by CR in the brain and liver is related to higher Ca²⁺ uptake rates and capacities, avoiding Ca²⁺-induced mitochondrial permeability transition. Dietary restriction has also been shown to increase kidney resistance against damaging stimuli; if these effects are related to similar mitochondrial adaptations has not been uncovered. Here, we characterized changes in mitochondrial function in response to 6 mo of CR in rats and measured bioenergetic parameters, redox balance, and Ca²⁺ homeostasis. CR promoted an increase in succinate-supported mitochondrial oxygen consumption rates. Although CR prevents mitochondrial reactive oxygen species production in many tissues, in kidney, we found that mitochondrial H₂O₂ release was enhanced in a succinate-dependent manner. Surprisingly, and opposite to the effects observed in the brain and liver, mitochondria from CR animals were more prone to Ca²⁺-induced mitochondrial permeability transition, in a manner reversed by the antioxidant dithiothreitol. CR mitochondria also displayed higher Ca²⁺ uptake rates, which were not accompanied by changes in Ca²⁺ efflux rates or related to altered inner mitochondrial membrane potentials or amounts of the mitochondrial Ca²⁺ uniporter. Instead, increased mitochondrial Ca²⁺ uptake rates in CR kidneys correlated with loss of mitochondrial Ca²⁺ uptake protein 2 (MICU2), a mitochondrial Ca²⁺ uniporter modulator. Interestingly, MICU2 is also modulated by CR in the liver, suggesting that it has a broader diet-sensitive regulatory role controlling mitochondrial Ca²⁺ homeostasis. Together, our results highlight the organ-specific bioenergetic, redox, and ionic transport results of CR, with some unexpected deleterious effects in the kidney.NEW & NOTEWORTHY Prevention of obesity through caloric restriction (CR) is well known to protect many tissues but has been poorly studied in kidneys. Here, we determined the effects of long-term CR in rat kidney mitochondria, which are central players in energy metabolism and aging. Surprisingly, we found that the diet increased mitochondrial reactive oxygen production and permeability transition. This suggests that the kidneys respond differently to restricted diets and may be more susceptible under CR.