An Impaired Respiratory Electron Chain Triggers Down-regulation of the Energy Metabolism and De-ubiquitination of Solute Carrier Amino Acid Transporters

Aretz, Ina; Hardt, Christopher; Wittig, Ilka; Meierhofer, David

doi:10.1074/mcp.m115.053181

Cited by 17 publications

(24 citation statements)

References 70 publications

(81 reference statements)

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“…By comparing the mtDNA reads between chRCC and controls, a significant and 3-fold decrease of the mtDNA content in chRCC was identified ( Figure 4j). This has been previously observed for chRCC (Meierhofer et al, 2004) and might be directly correlated to the abundance decrease of OXPHOS subunits, as similar observations in ρ 0 cells, entirely depleted of mtDNA, showed a severe reduction of all proteins involved in the respiratory chain (Aretz et al, 2016).…”

Section: Mtdna Mutations and Copy Number Variations In Chrccsupporting

confidence: 86%

Metabolic reprogramming and elevation of glutathione in chromophobe renal cell carcinomas

Xiao

Clima

Busch

et al. 2019

Preprint

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Chromophobe renal cell carcinomas (chRCC) are derived from intercalated cells of the collecting duct system, and are thought to be the malignant counterpart of benign renal oncocytomas.Here, we report the characterization of nine chRCC with adjacent healthy kidney tissues by applying proteome-, transcriptome (TCGA)-, and metabolome profiling. Most strikingly, the reactive oxygen species scavenger glutathione was significantly elevated in chRCC, caused by down-regulated enzymes involved in glutathione degradation. Metabolic reprogramming including stalled gluconeogenesis, down-regulated fatty acid-and amino acid metabolism was identified, even though, the abundance of amino acids and "energy carrier" molecules were unchanged. A striking anti-correlation of the mitochondrial respiratory chain between the transcriptome and the proteome was discovered, the transcripts coding for the respiratory chain were up-, while corresponding proteins and enzymatic activities were down-regulated. Similar to renal oncocytomas, chRCC exhibited a significant increase in glutathione, but are distinguishable by distinct regulation of the respiratory chain.

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Section: Mtdna Mutations and Copy Number Variations In Chrccsupporting

confidence: 86%

Metabolic reprogramming and elevation of glutathione in chromophobe renal cell carcinomas

Xiao

Clima

Busch

et al. 2019

Preprint

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“…Hence, the need to degrade defective oxidized transporters or proteins through the 26S proteasome via ubiquitination is reduced. This is supported by the global de-ubiquitination found in ρ 0 cells [21]. The molecular mechanism for the enhanced transporter activity in ρ 0 cells still remains to be discovered.…”

Section: Resultsmentioning

confidence: 81%

ρ0 Cells Feature De-Ubiquitination of SLC Transporters and Increased Levels and Fluxes of Amino Acids

Medina

Banaszczak

et al. 2017

IJMS

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Solute carrier (SLC) transporters are a diverse group of membrane transporter proteins that regulate the cellular flux and distribution of endogenous and xenobiotic compounds. Post-translational modifications (PTMs), such as ubiquitination, have recently emerged as one of the major regulatory mechanisms in protein function and localization. Previously, we showed that SLC amino acid transporters were on average 6-fold de-ubiquitinated and increased amino acid levels were detected in ρ0 cells (lacking mitochondrial DNA, mtDNA) compared to parental cells. Here, we elucidated the altered functionality of SLC transporters and their dynamic ubiquitination status by measuring the uptake of several isotopically labeled amino acids in both human osteosarcoma 143B.TK- and ρ0 cells. Our pulse chase analysis indicated that de-ubiquitinated amino acid transporters in ρ0 cells were accompanied by an increased transport rate, which leads to higher levels of amino acids in the cell. Finding SLC transport enhancers is an aim of the pharmaceutical industry in order to compensate for loss of function mutations in these genes. Thus, the ubiquitination status of SLC transporters could be an indicator for their functionality, but evidence for a direct connection between de-ubiquitination and transporter activity has to be further elucidated.

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“…r 0 cells are devoid of mtDNA and show drastic reduction of all ETC proteins (46). As a lower mtDNA copy number has been reported in chRCC (47), we speculated that the decreased levels of ETC complex subunits could be explained by a fewer number of copies of mtDNA.…”

Section: Decreased Mtdna Content and Mutations Lead To Oxphos Dysfuncmentioning

confidence: 72%

“…For example, the enzymatic activity of ETC complex subunits in chRCC and RO (15) corresponds to the abundance of the proteins and not gene expression. A study of mtDNA-depleted r 0 cells showed that the levels of all ETC components were significantly reduced because complex assembly is not possible without the core mtDNA-encoded subunits (46). Thus, the inverse relationship between transcript and protein levels in chRCC was mainly due to reduced mtDNA content.…”

Section: Discussionmentioning

confidence: 99%

Decreased Mitochondrial DNA Content Drives OXPHOS Dysregulation in Chromophobe Renal Cell Carcinoma

et al. 2020

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Chromophobe renal cell carcinoma (chRCC) and renal oncocytoma are closely related, rare kidney tumors. Mutations in complex I (CI)-encoding genes play an important role in dysfunction of the oxidative phosphorylation (OXPHOS) system in renal oncocytoma, but are less frequently observed in chRCC. As such, the relevance of OXPHOS status and role of CI mutations in chRCC remain unknown. To address this issue, we performed proteome and metabolome profiling as well as mitochondrial whole-exome sequencing to detect mitochondrial alterations in chRCC tissue specimens. Multiomic analysis revealed downregulation of electron transport chain (ETC) components in chRCC that differed from the expression profile in renal oncocytoma. A decrease in mitochondrial (mt)DNA content, rather than CI mutations, was the main cause for reduced OXPHOS in chRCC. There was a negative correlation between protein and transcript levels of nuclear DNAbut not mtDNA-encoded ETC complex subunits in chRCC. In addition, the reactive oxygen species scavenger glutathione (GSH) was upregulated in chRCC due to decreased expression of proteins involved in GSH degradation. These results demonstrate that distinct mechanisms of OXPHOS exist in chRCC and renal oncocytoma and that expression levels of ETC complex subunits can serve as a diagnostic marker for this rare malignancy. Significance: These findings establish potential diagnostic markers to distinguish malignant chRCC from its highly similar but benign counterpart, renal oncocytoma.

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An Impaired Respiratory Electron Chain Triggers Down-regulation of the Energy Metabolism and De-ubiquitination of Solute Carrier Amino Acid Transporters

Cited by 17 publications

References 70 publications

Metabolic reprogramming and elevation of glutathione in chromophobe renal cell carcinomas

Metabolic reprogramming and elevation of glutathione in chromophobe renal cell carcinomas

ρ0 Cells Feature De-Ubiquitination of SLC Transporters and Increased Levels and Fluxes of Amino Acids

Decreased Mitochondrial DNA Content Drives OXPHOS Dysregulation in Chromophobe Renal Cell Carcinoma

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