The Important Role and Implications of Citrate in the Composition, Structure, and Function of Oral/Periodontal/Craniofacial Tissues

Costello, Leslie C.; Franklin, Renty B.; Reynolds, Mark A.

doi:10.18689/mjdl-1000120

Cited by 9 publications

(8 citation statements)

References 30 publications

(42 reference statements)

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“…Of the relatively few cases described to date, one consistent finding is hypodontia and amelogenesis imperfecta ( 35 ), a phenotype replicated in the Slc13a5 −/− mice, consistent with a previous report ( 23 ). Like bone, teeth are assumed to contain high levels of citrate attributed to high citrate levels in dentin and cementum ( 36 ). In addition Slc13a5 is highly expressed in secretory ameloblasts ( 37 ) and ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth

Dirckx

Zhang

Chu

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Citrate is a critical metabolic substrate and key regulator of energy metabolism in mammalian cells. It has been known for decades that the skeleton contains most (>85%) of the body’s citrate, but the question of why and how this metabolite should be partitioned in bone has received singularly little attention. Here, we show that osteoblasts use a specialized metabolic pathway to regulate uptake, endogenous production, and the deposition of citrate into bone. Osteoblasts express high levels of the membranous Na + -dependent citrate transporter solute carrier family 13 member 5 ( Slc13a5 ) gene. Inhibition or genetic disruption of Slc13a5 reduced osteogenic citrate uptake and disrupted mineral nodule formation. Bones from mice lacking Slc13a5 globally, or selectively in osteoblasts, showed equivalent reductions in cortical thickness, with similarly compromised mechanical strength. Surprisingly, citrate content in mineral from Slc13a5 −/− osteoblasts was increased fourfold relative to controls, suggesting the engagement of compensatory mechanisms to augment endogenous citrate production. Indeed, through the coordinated functioning of the apical membrane citrate transporter SLC13A5 and a mitochondrial zinc transporter protein (ZIP1; encoded by Slc39a1 ), a mediator of citrate efflux from the tricarboxylic acid cycle, SLC13A5 mediates citrate entry from blood and its activity exerts homeostatic control of cytoplasmic citrate. Intriguingly, Slc13a5 -deficient mice also exhibited defective tooth enamel and dentin formation, a clinical feature, which we show is recapitulated in primary teeth from children with SLC13A5 mutations. Together, our results reveal the components of an osteoblast metabolic pathway, which affects bone strength by regulating citrate deposition into mineral hydroxyapatite.

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Section: Discussionmentioning

confidence: 99%

“…6 G ). Enamel is the hardest mineral tissue in the body and contains no collagen ( 36 ). Dentin and cementum, however, exhibit a mineral/collagen complex that is more comparable to bone ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth

Dirckx

Zhang

Chu

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Thus, through this so-called Randle cycle regulation [ 7 ], glycolysis is nearly switched off, while fat degradation, gluconeogenesis and the production of glucose are favoured [ 2 ]. Moreover, citrate is involved in numerous physiological processes and regulations, such as insulin secretion [ 9 ], prostatic fluid and spermatozoid mobility [ 10 ], the formation and strength of dental and bone tissues [ 11 , 12 ], immune and inflammatory response, and anti-bacterial defence [ 13 , 14 , 15 , 16 , 17 ]. Consequently, the deregulation of citrate metabolism is observed in various pathologies, particularly obesity, diabetes, inflammation, and cancer.…”

Section: Introductionmentioning

confidence: 99%

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Icard

Coquerel

et al. 2021

IJMS

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Citrate plays a central role in cancer cells’ metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies.

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“…E) Carboxylate ions can only be incorporated into the hydrated layer of CaP The status of citrate in apatite/collagen component of bone. The image is inspired by the artwork of (Costello et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…FIGURE 7The status of citrate in apatite/collagen component of bone. The image is inspired by the artwork of(Costello et al, 2018).…”

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confidence: 99%

Role of carboxylic organic molecules in interfibrillar collagen mineralization

Indurkar

Choudhary

Rubenis

et al. 2023

Front. Bioeng. Biotechnol.

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Bone is a composite material made up of inorganic and organic counterparts. Most of the inorganic counterpart accounts for calcium phosphate (CaP) whereas the major organic part is composed of collagen. The interfibrillar mineralization of collagen is an important step in the biomineralization of bone and tooth. Studies have shown that synthetic CaP undergoes auto-transformation to apatite nanocrystals before entering the gap zone of collagen. Also, the synthetic amorphous calcium phosphate/collagen combination alone is not capable of initiating apatite nucleation rapidly. Therefore, it was understood that there is the presence of a nucleation catalyst obstructing the auto-transformation of CaP before entering the collagen gap zone and initiating rapid nucleation after entering the collagen gap zone. Therefore, studies were focused on finding the nucleation catalyst responsible for the regulation of interfibrillar collagen mineralization. Organic macromolecules and low-molecular-weight carboxylic compounds are predominantly present in the bone and tooth. These organic compounds can interact with both apatite and collagen. Adsorption of the organic compounds on the apatite nanocrystal governs the nucleation, crystal growth, lattice orientation, particle size, and distribution. Additionally, they prevent the auto-transformation of CaP into apatite before entering the interfibrillar compartment of the collagen fibril. Therefore, many carboxylic organic compounds have been utilized in developing CaP. In this review, we have covered different carboxylate organic compounds governing collagen interfibrillar mineralization.

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The Important Role and Implications of Citrate in the Composition, Structure, and Function of Oral/Periodontal/Craniofacial Tissues

Cited by 9 publications

References 30 publications

A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth

A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

Role of carboxylic organic molecules in interfibrillar collagen mineralization

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