Rats fed prolonged high protein diets show an increase in nitrogen metabolism and liver megamitochondria

Zaragozá, Remedios; Renau‐Piqueras, Jaime; Portolés, Manuel; Hernández-Yago, José; Jordá, A.; Grisolı́a, Santiago

doi:10.1016/0003-9861(87)90364-x

Cited by 40 publications

(20 citation statements)

References 25 publications

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“…It should be noted that megamitochondria can also be produced by a high protein diet (57). Such high protein diets may cause an increase in the intracellular amino acid levels and presumably the level of glutamine.…”

Section: Discussionmentioning

confidence: 99%

Elevation of Glutamine Level by Selenophosphate Synthetase 1 Knockdown Induces Megamitochondrial Formation in Drosophila Cells

Shim

Kim

Jung

et al. 2009

Journal of Biological Chemistry

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Although selenophosphate synthetase 1 (SPS1/SelD) is an essential gene in Drosophila, its function has not been determined. To elucidate its intracellular role, we targeted the removal of SPS1/SelD mRNA in Drosophila SL2 cells using RNA interference technology that led to the formation of vacuole-like globular structures. Surprisingly, these structures were identified as megamitochondria, and only depolarized mitochondria developed into megamitochondria. The mRNA levels of l(2)01810 and glutamine synthetase 1 (GS1) were increased by SPS1/SelD knockdown. Blocking the expression of GS1 and l(2)01810 completely inhibited the formation of megamitochondria induced by loss of SPS1/SelD activity and decreased the intracellular levels of glutamine to those of control cells suggesting that the elevated level of glutamine is responsible for megamitochondrial formation. Overexpression of GS1 and l(2)01810 had a synergistic effect on the induction of megamitochondrial formation and on the synthesis of glutamine suggesting that l(2)01810 is involved in glutamine synthesis presumably by activating GS1. Our results indicate that, in Drosophila, SPS1/SelD regulates the intracellular glutamine by inhibiting GS1 and l(2)01810 expression and that elevated levels of glutamine lead to a nutritional stress that provides a signal for megamitochondrial formation.Selenium is an essential trace element in the diet of humans and many other life forms. It provides many health benefits such as roles in preventing cancer and heart disease, serving as an antiviral agent, stimulating the immune system, reactive oxygen species (ROS) 4 scavenging, and male reproduction (1-6). Many of the benefits of selenium are most likely due to the presence of this element in selenoproteins as the amino acid selenocysteine (Sec) (7-9). Sec is the 21st amino acid in the genetic code (10 -12) and is incorporated into selenoproteins in response to UGA Sec codons (13,14). The active donor of selenium in Sec biosynthesis is monoselenophosphate (15), which is synthesized from selenite and ATP by an enzyme designated as selenophosphate synthetase (SPS) (16). There are two isoforms of SPS in higher eukaryotes, SPS1/SelD and SPS2, whereas only one type of SPS (SelD) exists in lower eukaryotes and eubacteria (17). The sequences of SPS1/SelD and SPS2 are highly conserved. For example, the amino acid sequence homology between human SPS1/SelD and SPS2 is 72% and that between Drosophila SPS1/SelD and SPS2 is ϳ45%. One of the major differences between SPS1/SelD and SPS2 is that SPS1/ SelD has an arginine at the position corresponding to Sec in SPS2 (18,19).Initially, both SPS1/SelD and SPS2 were thought to be involved in selenophosphate synthesis. However, it was subsequently shown that only SPS2 catalyzes selenophosphate synthesis. In in vitro experiments, SPS2 synthesized selenophosphate from selenide and ATP, but SPS1/SelD did not have this activity (20). Knockdown of SPS2 in NIH3T3 cells led to the loss of selenoprotein biosynthesis, whereas the inhibition of SPS1/ SelD...

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Section: Discussionmentioning

confidence: 99%

Elevation of Glutamine Level by Selenophosphate Synthetase 1 Knockdown Induces Megamitochondrial Formation in Drosophila Cells

Shim

Kim

Jung

et al. 2009

Journal of Biological Chemistry

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“…Several enzymes involved in nitrogen metabolism and the urea cycle also changed in response to the CBS mutation and/or HM diet. High protein diets generally result in significant increases in the concentrations of the urea cycle enzymes (67) to catabolize the excess nitrogen provided by the diet. Homocystinurics may also be in a state of excess nitrogen as a consequence of their hypermethioninemia.…”

Section: Discussionmentioning

confidence: 99%

The Nutrigenetics of Hyperhomocysteinemia

DiBello

Dayal

Kaveti

et al. 2010

Molecular & Cellular Proteomics

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Hyperhomocysteinemia has long been associated with atherosclerosis and thrombosis and is an independent risk factor for cardiovascular disease. Its causes include both genetic and environmental factors. Although homocysteine is produced in every cell as an intermediate of the methionine cycle, the liver contributes the major portion found in circulation, and fatty liver is a common finding in homocystinuric patients. To understand the spectrum of proteins and associated pathways affected by hyperhomocysteinemia, we analyzed the mouse liver proteome of gene-induced (cystathionine ␤-synthase (CBS)) and diet-induced (high methionine) hyperhomocysteinemic mice using two-dimensional difference gel electrophoresis and Ingenuity Pathway Analysis. Nine proteins were identified whose expression was significantly changed by 2-fold (p < 0.05) as a result of genotype, 27 proteins were changed as a result of diet, and 14 proteins were changed in response to genotype and diet. Importantly, three enzymes of the methionine cycle were upregulated. S-Adenosylhomocysteine hydrolase increased in response to genotype and/or diet, whereas glycine Nmethyltransferase and betaine-homocysteine methyltransferase only increased in response to diet. The antioxidant proteins peroxiredoxins 1 and 2 increased in wild-type mice fed the high methionine diet but not in the CBS mutants, suggesting a dysregulation in the antioxidant capacity of those animals. Furthermore, thioredoxin 1 decreased in both wild-type and CBS mutants on the diet but not in the mutants fed a control diet. Several urea cycle proteins increased in both diet groups; however, arginase 1 decreased in the CBS ؉/؊ mice fed the control diet. Pathway analysis identified the retinoid X receptor signaling pathway as the top ranked network associated with the CBS ؉/؊ genotype, whereas xenobiotic metabolism and the NRF2-mediated oxidative stress response were associated with the high methionine diet. Our results show that hyperhomocysteinemia, whether caused by a genetic mutation or diet, alters the abundance of several liver proteins involved in homocysteine/methionine metabolism, the urea cycle, and antioxidant defense. Molecular & Cellular Proteomics 9:471-485, 2010.

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“…Hypertrophy of mitochondria is another possible mechanism of the formation of MG. However, there is only one report in the literature describing the induction of MG in rat livers by feeding animals with a high-protein diet [217]. Disturbance in the dividing process of mitochondria may result in the formation of MG. Chloramphenicol-induced formation of MG has been accepted as a typical example, since it is known to specifically inhibit protein synthesis in mitochondria.…”

Section: Membrane Fusion As a Mechanism For The Mg Formationmentioning

confidence: 99%

Megamitochondria formation ‐ physiology and pathology

Wakabayashi

2002

J Cellular Molecular Medi

163

120

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Mitochondria undergo structural changes simultaneously with their functional changes in both physiological and pathological conditions. These structural changes of mitochondria are classified into two categories: simple swelling and the formation of megamitochondria (MG). Data have been accumulated to indicate that free radicals play a crucial role in the mechanism of the MG formation induced by various experimental conditions which are apparently various. These include ethanol-, chloramphenicol-and hydrazine-induced MG formation. Involvement of free radicals in the mechanism of MG formation is showed by the fact that MG formation is successfully suppressed by free radical scavengers such as α-tocopherol, coenzyme Q 10 , and 4-OH-TEMPO. Detailed mechanisms and pathophysiological meanings of MG formation still remain to be investigated. However, a body of evidence strongly suggests that enormous changes in physicochemical and biochemical properties of the mitochondrial membranes during MG formation take place and these changes are favorable for membrane fusion. A recent report showed that continous exposure of cells with MG to free radicals induces apoptosis, finding which suggests that MG formation is an adaptative process to unfavorable environments at the level of intracellular organelles. Mitochondria try to decrease intracellular reactive oxygen species (ROS) levels by decreasing the consume of oxygen via MG formation. If mitochondria succeed to suppress intracellular ROS levels, MG return to normal both structurally and functionally, and they restore the ability to actively synthesize ATP. If cells are additionally exposed to excess amounts of free radicals, MG become swollen, membrane potential of mitochondria (∆Ψm) decreases, cytochrome c is released from mitochondria, leading to activation of caspases and apoptosis is induced.

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Rats fed prolonged high protein diets show an increase in nitrogen metabolism and liver megamitochondria

Cited by 40 publications

References 25 publications

Elevation of Glutamine Level by Selenophosphate Synthetase 1 Knockdown Induces Megamitochondrial Formation in Drosophila Cells

Elevation of Glutamine Level by Selenophosphate Synthetase 1 Knockdown Induces Megamitochondrial Formation in Drosophila Cells

The Nutrigenetics of Hyperhomocysteinemia

Megamitochondria formation ‐ physiology and pathology

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