Multiple roles played by the mitochondrial citrate carrier in cellular metabolism and physiology

Zara, Vincenzo; Assalve, Graziana; Ferramosca, Alessandra

doi:10.1007/s00018-022-04466-0

Cited by 18 publications

(8 citation statements)

References 96 publications

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“…12 Specifically, the mitochondrial citrate carrier (CIC) is responsible for transporting citrate across the inner mitochondrial matrix into the cytoplasm in exchange for malate. 27,28 Following export of citrate across the inner mitochondrial matrix, it is converted to cytoplasmic acetyl-CoA through the action of ATP citrate lyase (ACLY). Alternatively, cytoplasmic acetyl-CoA can be produced from acetate via ACSS2 (Figure 2A) .…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

Mahr

Jena

Nashif

et al. 2023

Preprint

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Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.

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Section: Resultsmentioning

confidence: 99%

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

Mahr

Jena

Nashif

et al. 2023

Preprint

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“…Import and export of metabolites through the inner mitochondrial membrane require mitochondrial transport proteins 12 . Specifically, the mitochondrial citrate carrier (CIC) is responsible for transporting citrate across the inner mitochondrial matrix into the cytoplasm in exchange for malate 27 , 28 . Following export of citrate across the inner mitochondrial matrix, it is converted to cytoplasmic acetyl-CoA through the action of ATP citrate lyase (ACLY).…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial citrate metabolism and efflux regulate BeWo differentiation

Mahr

Jena

Nashif

et al. 2023

Sci Rep

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Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established BeWo cell culture model of trophoblast differentiation. Differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.

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“…Cytosolic Cit concentrations are typically low due to their rapid turnover [ 82 ]. The Ce4-concentration-dependent increase in Cit levels indicates an imbalance that can be caused by both enhanced Cit synthesis and enhanced mitochondrial release via the Cit carrier membrane protein [ 83 ] or reduced Cit consumption in the cytosol. OAA is, among others, also converted into Asp for nucleotide and polyamine synthesis.…”

Section: Resultsmentioning

confidence: 99%

Intracellular Fate of the Photosensitizer Chlorin e4 with Different Carriers and Induced Metabolic Changes Studied by 1H NMR Spectroscopy

Vermathen,

Kämpfer,

Nuoffer

et al. 2023

Pharmaceutics

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Porphyrinic photosensitizers (PSs) and their nano-sized polymer-based carrier systems are required to exhibit low dark toxicity, avoid side effects, and ensure high in vivo tolerability. Yet, little is known about the intracellular fate of PSs during the dark incubation period and how it is affected by nanoparticles. In a systematic study, high-resolution magic angle spinning NMR spectroscopy combined with statistical analyses was used to study the metabolic profile of cultured HeLa cells treated with different concentrations of PS chlorin e4 (Ce4) alone or encapsulated in carrier systems. For the latter, either polyvinylpyrrolidone (PVP) or the micelle-forming polyethylene glycol (PEG)-polypropylene glycol triblock copolymer Kolliphor P188 (KP) were used. Diffusion-edited spectra indicated Ce4 membrane localization evidenced by Ce4 concentration-dependent chemical shift perturbation of the cellular phospholipid choline resonance. The effect was also visible in the presence of KP and PVP but less pronounced. The appearance of the PEG resonance in the cell spectra pointed towards cell internalization of KP, whereas no conclusion could be drawn for PVP that remained NMR-invisible. Multivariate statistical analyses of the cell spectra (PCA, PLS-DA, and oPLS) revealed a concentration-dependent metabolic response upon exposure to Ce4 that was attenuated by KP and even more by PVP. Significant Ce4-concentration-dependent alterations were mainly found for metabolites involved in the tricarboxylic acid cycle and the phosphatidylcholine metabolism. The data underline the important protective role of the polymeric carriers following cell internalization. Moreover, to our knowledge, for the first time, the current study allowed us to trace intracellular PS localization on an atomic level by NMR methods.

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Multiple roles played by the mitochondrial citrate carrier in cellular metabolism and physiology

Cited by 18 publications

References 96 publications

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation

Mitochondrial citrate metabolism and efflux regulate BeWo differentiation

Intracellular Fate of the Photosensitizer Chlorin e4 with Different Carriers and Induced Metabolic Changes Studied by 1H NMR Spectroscopy

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