Maternal Protein Restriction in Two Successive Generations Impairs Mitochondrial Electron Coupling in the Progeny’s Brainstem of Wistar Rats From Both Sexes

Abstract

Maternal protein deficiency during the critical development period of the progeny disturbs mitochondrial metabolism in the brainstem, which increases the risk of developing cardiovascular diseases in the first-generation (F1) offspring, but is unknown if this effect persists in the second-generation (F2) offspring. The study tested whether mitochondrial health and oxidative balance will be restored in F2 rats. Male and female rats were divided into six groups according to the diet fed to their mothers throughout gestation and lactation periods. These groups were: (1) normoprotein (NP) and (2) low-protein (LP) rats of the first filial generation (F1-NP and F1-LP, respectively) and (3) NP and (4) LP rats of the second filial generation (F2-NP and F2-LP, respectively). After weaning, all groups received commercial chow and a portion of each group was sacrificed on the 30th day of life for determination of mitochondrial and oxidative parameters. The remaining portion of the F1 group was mated at adulthood and fed an NP or LP diet during the periods of gestation and lactation, to produce progeny belonging to (5) F2R-NP and (6) F2R-LP group, respectively. Our results demonstrated that male F1-LP rats suffered mitochondrial impairment associated with an 89% higher production of reactive species (RS) and 137% higher oxidative stress biomarkers, but that the oxidative stress was blunted in female F1-LP animals despite the antioxidant impairment. In the second generation following F0 malnutrition, brainstem antioxidant defenses were restored in the F2-LP group of both sexes. However, F2R-LP offspring, exposed to LP in the diets of the two preceding generations displayed a RS overproduction with a concomitant decrease in mitochondrial bioenergetics. Our findings demonstrate that nutritional stress during the reproductive life of the mother can negatively affect mitochondrial metabolism and oxidative balance in the brainstem of F1 progeny, but that restoration of a normal diet during the reproductive life of those individuals leads toward a mitochondrial recovery in their own (F2) progeny. Otherwise, if protein deprivation is continued from the F0 generation and into the F1 generation, the F2 progeny will exhibit no recovery, but instead will remain vulnerable to further oxidative damage.

Low Nephron Number Induced by Maternal Protein Restriction Is Prevented by Nicotinamide Riboside Supplementation Depending on Sirtuin 3 Activation

“…Given the profound alteration in the acetylation status of mitochondrial proteins, we investigated the mitochondrial ultrastructure. Consistent with previous studies on the liver and skeletal muscle [ 35 , 36 , 37 , 38 , 39 ], we found that exposure to a maternal LP diet had a negative impact on mitochondrial structure in the neonatal kidney. In this setting, NR significantly rescued defects in mitochondrial morphology, which is recognized as being strictly connected with key mitochondrial functions.…”

“…There is evidence that exposure to a maternal LP diet has a great impact on mitochondrial activity, including impairment of mitochondrial functions [ 35 , 36 , 37 , 38 , 39 ]. Having identified marked alterations in mitochondrial proteins in maternal LP offspring, we sought to analyze mitochondrial ultrastructure with TEM.…”

Low Protein Programming Causes Increased Mitochondrial Fusion and Decreased Oxygen Consumption in the Hepatocytes of Female Rats

“…Our TEM data show that the number of fused mitochondria was higher in the liver of LP offspring when compared with the controls, indicating impaired hepatic mitochondrial dynamics. Recent studies have provided much evidence to consider the mitochondria as one of the potential targets for the in utero programming of adult diseases [ 29 , 30 , 31 , 32 ]. However, the molecular mechanisms leading to unregulated glucose metabolism are not well studied.…”

Modulation of Energy Metabolism and Epigenetic Landscape in Rainbow Trout Fry by a Parental Low Protein/High Carbohydrate Diet

“…Mitochondria, the powerhouse of the cell, are dynamic organelles that can either fuse to create more elongated mitochondria or a mitochondrial network, or undergo fission, thus creating a fragmented mitochondrial network. In murine species, maternal nutrient insults, such as a high sugar diet or a LP diet, typically induce unbalanced mitochondrial fusion/fission, leading to mitochondrial dysfunction in offspring across different generations [57][58][59][60][61]. In addition to the previous results regarding bioenergetics, qPCR also revealed that relative mRNA levels in genes coding for Bnip3 (log2FC = −0.13 between NH and NN), Opa1 (log2FC = −0.18 between HH and NN), and Fis (log2FC = −0.14 between HH and NN), proteins that orchestrate either mitochondrial fusion or fission, were slightly affected by the parental HC/LP diet.…”