Cellular signaling of amino acids towards mTORC1 activation in impaired human leucine catabolism

Schriever, Sonja C.; Deutsch, Manuel J.; Adamski, Jerzy; Roscher, Adelbert A.; Ensenauer, Regina

doi:10.1016/j.jnutbio.2012.04.018

Cited by 40 publications

(38 citation statements)

References 37 publications

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“…We analyzed de novo mitochondrial protein synthesis in cells where AUH was knocked down, or where mutant or wild-type AUH were overexpressed, in the presence of normal or excess leucine by 35S-labeled incorporation of methionine and cysteine in the 13 proteins encoded by the mitochondrial genome. We found that leucine treatment alone decreased mitochondrial translation, unlike the stimulatory effect that leucine has on cytoplasmic translation (Figure 7) (27). Moreover, we observed a significant overall decrease of mitochondrial protein synthesis when AUH was overexpressed or knocked down in cells compared to controls as seen previously (Figure 2B), and this decrease was more pronounced in the presence of leucine (Figure 7A and B ).…”

Section: Resultsmentioning

confidence: 87%

“…The amino acid leucine has been shown to stimulate protein synthesis by cytoplasmic ribosomes (27). Since AUH has been shown to catalyze the conversion of an intermediate substrate in the leucine degradation pathway (28), we investigated the effect of leucine on protein synthesis in mitochondria and if the role of AUH in leucine catabolism affects this process.…”

Section: Resultsmentioning

confidence: 99%

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A bifunctional protein regulates mitochondrial protein synthesis

Richman

Davies

Shearwood

et al. 2014

Nucleic Acids Research

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Mitochondrial gene expression is predominantly regulated at the post-transcriptional level and mitochondrial ribonucleic acid (RNA)-binding proteins play a key role in RNA metabolism and protein synthesis. The AU-binding homolog of enoyl-coenzyme A (CoA) hydratase (AUH) is a bifunctional protein with RNA-binding activity and a role in leucine catabolism. AUH has a mitochondrial targeting sequence, however, its role in mitochondrial function has not been investigated. Here, we found that AUH localizes to the inner mitochondrial membrane and matrix where it associates with mitochondrial ribosomes and regulates protein synthesis. Decrease or overexpression of the AUH protein in cells causes defects in mitochondrial translation that lead to changes in mitochondrial morphology, decreased mitochondrial RNA stability, biogenesis and respiratory function. Because of its role in leucine metabolism, we investigated the importance of the catalytic activity of AUH and found that it affects the regulation of mitochondrial translation and biogenesis in response to leucine.

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Section: Resultsmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 99%

A bifunctional protein regulates mitochondrial protein synthesis

Richman

Davies

Shearwood

et al. 2014

Nucleic Acids Research

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“…35 IGF1R, MAP4K3, and Bcl-xl are involved in the mTOR signaling pathway, which plays a role in angiogenesis and cell migration. 36,37 We speculated that let-7c might regulate MMD through angiogenesis and vessel reconstruction.…”

Section: Discussionmentioning

confidence: 99%

Elevated Serum MicroRNA Let-7c in Moyamoya Disease

Zhao

Gong

Zhang

et al. 2015

Journal of Stroke and Cerebrovascular Diseases

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“…Whether or not BCATc impacts mTOR signalling, through modulation of leucine/KIC concentrations or influencing α-ketoglutarate concentrations, remains to be determined. A recent publication suggests that leucine and not leucine metabolites are key regulators [37]. However, the lack of BCATc in T lymphocytes, which prevents induction of BCATc during T cell receptor engagement, strongly influences mTOR signalling leading to higher mTORC1 activation (unpublished data).…”

Section: Metabolite Shuttling In Peripheral Bcaa Metabolismmentioning

confidence: 97%

The Cytosolic and Mitochondrial Branched Chain Aminotransferase

Conway

Hutson

2015

Branched Chain Amino Acids in Clinical Nutrition

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Key Points• The branched chain aminotransferases (BCAT) are PLP-dependent proteins which catalyze the transfer of an amino group from the donor amino acid to α-ketoglutarate, forming glutamate and the respective keto acids.• Structurally the BCAT proteins are homodimers, where the active site between each isoform is largely conserved.• The cytosolic and mitochondrial isoforms show cell and tissue specific expression where the aminotransferase proteins play an integrated role in shuttling metabolites between cells and tissues.• These anaplerotic shuttles interface with core metabolic pathways and protein complexes such as the branched chain α-keto acid dehydrogenase complex and glutamate dehydrogenase, respectively, indicating a role in the regeneration of key metabolites such as the primary neurotransmitter glutamate.• Leucine is a nutrient signal and involved in mTOR signalling, which controls the synthesis of cellular protein levels. • Moreover, the BCAT proteins have a unique redox-active CXXC motif regulated through changes in the redox environment, likely to play a key role in this signalling mechanism. • Site-directed mutagenesis studies have identified that the N-terminal cysteine acts as the 'redox sensor' and the C-terminal cysteine as its resolving partner, which permits reversible regulation.• Oxidation, S-nitrosation and S-glutathionylation are important redox regulators of BCAT activity and are reversibly controlled through the glutaredoxin/glutathione system. • Biochemical and X-ray crystallography studies of the redox-active mutant proteins describe the importance of the N-terminal cysteine in the orientation of the substrate and its interaction with key residues of the interdomain loop.

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Cellular signaling of amino acids towards mTORC1 activation in impaired human leucine catabolism

Cited by 40 publications

References 37 publications

A bifunctional protein regulates mitochondrial protein synthesis

A bifunctional protein regulates mitochondrial protein synthesis

Elevated Serum MicroRNA Let-7c in Moyamoya Disease

The Cytosolic and Mitochondrial Branched Chain Aminotransferase

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