Regulation of kidney mitochondrial function by caloric restriction

Abstract

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 calcium uptake rates and capacities, avoiding Ca2+-induced mitochondrial permeability transition. Dietary restriction has also been shown to increase kidney resistance against damaging stimuli, but if these effects are related to similar mitochondrial adaptations has not been uncovered. Here, we characterized changes in mitochondrial function in response to six months CR in rats, measuring bioenergetic parameters, redox balance and calcium homeostasis. CR promoted an increase in succinate-supported mitochondrial oxygen consumption rates. While 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 brain and liver, mitochondria from CR animals are more prone to Ca2+-induced mitochondrial permeability transition, in a manner reversed by antioxidant dithiothreitol. CR mitochondria also displayed higher calcium uptake rates, which were not accompanied by changes in calcium efflux rates, nor related to altered inner mitochondrial membrane potentials or amounts of the mitochondrial calcium uniporter (MCU). Instead, increased mitochondrial calcium uptake rates in CR kidneys correlate with a loss of MICU2, an MCU modulator. Interestingly, MICU2 is also modulated by CR in liver, suggesting it has a broader diet-sensitive regulatory role controlling mitochondrial calcium homeostasis. Together, our results highlight the organ-specific bioenergetic, redox, and ionic transport effects of CR, with some unexpected deleterious effects in kidney.

Mitochondrial sodium/calcium exchanger (NCLX) regulates basal and starvation‐induced autophagy through calcium signaling

“…Autophagy is mainly activated in response to decreased nutrient availability 17 . Interestingly, works published by our group have shown that mitochondrial Ca 2+ transport is strongly regulated by nutritional interventions such as caloric restriction, which is also well known to promote autophagy 30,40,41 . As a starting point to understand the interplay between mitochondrial Ca 2+ transport and autophagy, we investigated whether NCLX levels are sensitive to calorie restriction.…”

“…17 Interestingly, works published by our group have shown that mitochondrial Ca 2+ transport is strongly regulated by nutritional interventions such as caloric restriction, which is also well known to promote autophagy. 30,40,41 As a starting point to understand the interplay between mitochondrial Ca 2+ transport and autophagy, we investigated whether NCLX levels are sensitive to calorie restriction. We consistently observed that mitochondria isolated from the livers of mice that underwent 4 months of caloric restriction contained higher levels of NCLX protein than animals on an ad libitum diet (Figure 1A).…”

Mitochondrial Sodium/Calcium Exchanger (NCLX) Regulates Basal and Starvation-Induced Autophagy Through Calcium Signaling

“…Autophagy is mainly activated in response to decreased nutrient availability (Lahiri et al, 2019). Interestingly, works published by our group have shown that mitochondrial Ca 2+ transport is strongly regulated by nutritional interventions such as caloric restriction, which is also well known to promote autophagy (Menezes-Filho et al, 2017; Amigo et al, 2017; Serna et al, 2022). As a starting point to understand the interplay between mitochondrial Ca 2+ transport and autophagy, we investigated whether NCLX levels are sensitive to calorie restriction.…”

“…After the diet period, mitochondria were isolated from the livers of mice as described previously (Serna et al, 2022). Briefly, the livers were minced, washed repeatedly with ice-cold PBS and suspended in isolation buffer (250 mM sucrose, 10 mM HEPES, 1 mM EGTA, 1 mM EDTA, 1 mg/ml BSA fatty acid-free).…”

The Nicotinamide/Streptozotocin Rodent Model of Type 2 Diabetes: Renal Pathophysiology and Redox Imbalance Features

“…Finally, this NA-STZ diabetes animal model may also be used to evaluate any potential renoprotective effects of caloric restriction [ 142 , 143 , 144 ], intermittent caloric restriction [ 145 , 146 ], exercise [ 147 , 148 , 149 , 150 ], and ketone bodies [ 151 , 152 , 153 , 154 ], which all have been demonstrated to provide beneficial effects on the kidney in a variety of pathological conditions [ 155 , 156 ]. Indeed, the underlying mechanisms of renoprotection conferred by these approaches in this non-obese type 2 diabetes model remain to be comprehensively elucidated.…”