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Mitochondrial VHL rewires cell metabolism in hypoxia

ABSTRACT: Under normoxia, von Hippel-Lindau (VHL) protein targets the oxygen-induced, hydroxylated form of hypoxia-inducible factors for degradation to orchestrate mammalian oxygen sensing. However, whether VHL plays non-canonical roles in hypoxia, when protein hydroxylation is attenuated, remains elusive. Here we show that most cytosolic VHL is degraded under chronic hypoxia, with the remaining VHL pool primarily translocating to the mitochondria. Mitochondrial VHL binds and inhibits MCCC2, an essential subunit of leucine catabolic machinery. Accumulated leucine allosterically activates glutamate dehydrogenase to promote glutaminolysis, generating sufficient lipids and nucleotides to support hypoxic cell growth. Furthermore, SRC-mediated VHL phosphorylation and PRMT5-mediated MCCC2 methylation synergistically regulate the VHL-MCCC2 interaction and concomitant metabolic changes, which are recapitulated in animal models of pathological hypoxia and functionally associated with VHL mutation subtypes in cancer.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: 李国邦

LAB HEAD: LI GUOBANG

PROVIDER: PXD056376 | Pride | 2025-08-26

REPOSITORIES: Pride

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			Action	DRS
	480_FPEP230034826-1A.raw	Raw
	480_FPEP230034826-1A_PeptideGroups.txt	Txt
	480_FPEP230034826-1A_Proteins.txt	Txt
	480_FPEP230034827-1A.raw	Raw
	480_FPEP230034827-1A_PeptideGroups.txt	Txt

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Mitochondrial VHL rewires cell metabolism in hypoxia

Project description:Under normoxia, von Hippel-Lindau (VHL) protein targets the oxygen-induced, hydroxylated form of hypoxia-inducible factors for degradation to orchestrate mammalian oxygen sensing. However, whether VHL plays non-canonical roles in hypoxia, when protein hydroxylation is attenuated, remains elusive. Here we show that most cytosolic VHL is degraded under chronic hypoxia, with the remaining VHL pool primarily translocating to the mitochondria. Mitochondrial VHL binds and inhibits MCCC2, an essential subunit of leucine catabolic machinery. Accumulated leucine allosterically activates glutamate dehydrogenase to promote glutaminolysis, generating sufficient lipids and nucleotides to support hypoxic cell growth. Furthermore, SRC-mediated VHL phosphorylation and PRMT5-mediated MCCC2 methylation synergistically regulate the VHL-MCCC2 interaction and concomitant metabolic changes, which are recapitulated in animal models of pathological hypoxia and functionally associated with VHL mutation subtypes in cancer.

2025-09-01 | PXD053354 | Pride

VHL acts as an adaptor to promote the phosphorylation of FTO by CK2 to suppress clear cell renal cell carcinoma

Project description:Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark feature of ccRCC, a clear cell renal cell carcinoma. However, elucidating how VHL loss drives ccRCC pathogenesis remains challenging. As the most abundant posttranscriptional modification of mRNA in eukaryotes, N6-methyladenine (m6A) is involved in the posttranscriptional regulation of mRNA molecules and has been found to play an important role in the biological process of tumorigenesis and cancer progression. Here, we show that VHL has a protein interaction with the m6A demethylase FTO, but does not perform the classical function of targeting FTO for ubiquitination degradation. Rather, VHL acts as an adapter that promotes CK2 phosphorylation of FTO, thereby regulating the enzymatic activity of FTO. MeRIP-Seq and RNA-seq sequencing analyses identified EGR1 as one of the FTO targets for VHL-deficient ccRCC cell survival. Mechanistically, FTO in ccRCC decreases the m6A level of EGR1 and inhibits EGR1 and P53 protein levels, thereby promoting ccRCC proliferation. In summary, our study identified FTO as a potential non-hypoxia inducible factor (HIF) classical substrate of VHL, highlighted the critical role of FTO in regulating m6A levels in ccRCC progression, and identified the CK2-FTO-EGR1-P53 regulatory axis as a potential target for the treatment of VHL-deficient ccRCC.

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Deciphering functions of VHL in Clear Cell Renal Cell Carcinoma

Project description:VHL is the most frequently mutated gene in ccRCC.It functions via the oxygen-dependent ubiquitin-mediated degradation of hypoxia-inducible factor (HIF). The stabilization and hyperactivation of HIF1 play essential roles in tumorigenesis. This is a TMT based proteomics experiment aimed to investigate the functions of VHL in ccRCC systematically.

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Gene expression analysis in response to hypoxic pathway inhibition

Project description:Gene expression analysis of HeLa cells exposed to hypoxia (1% Oxygen), treated with a PHD inhibitor (IOX2) or treated with a VHL inhibitor (VH032) for 16 hours

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Von Hippel-Lindau protein is required for optimal alveolar macrophage terminal differentiation, self-renewal and function.

Project description:The rapid transit from hypoxia to normoxia in the lung that follows the first breath in newborn mice coincides with alveolar macrophage (AM) differentiation. However, whether sensing of oxygen affects AM maturation and function has not been previously explored. We have generated mice whose AMs show a deficient ability to sense oxygen after birth by deleting Vhl, a negative regulator of HIF transcription factors, in the CD11c compartment (CD11c∆Vhl mice). VHL-deficient AMs show an immature-like phenotype and an impaired self-renewal capacity in vivo that persists upon culture ex vivo. VHL-deficient phenotype is intrinsic in AMs derived from monocyte precursors in mixed bone marrow chimeras. Moreover, unlike control Vhlfl/fl, AMs from CD11c∆Vhl mice do not revert pulmonary alveolar proteinosis when transplanted into Csf2rb-/- mice, demonstrating that VHL contributes to AM-mediated surfactant clearance. Thus, our results suggest that optimal AM terminal differentiation, self-renewal, and homeostatic function requires their oxygen sensing capacity.

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Hypoxia stabilizes SETDB1 to maintain genome stability

Project description:Von Hippel-Lindau (VHL) is a tumor suppressor that functions as the substrate recognition subunit of the CRL2VHL E3 complex. While substrates of VHL have been identified, its tumor suppressive role remains to be fully understood. For further determination of VHL substrates, we analyzed the physical interactome of VHL and identified the histone H3K9 methyltransferase SETBD1 as a novel target. SETDB1 undergoes oxygen-dependent hydroxylation by prolyl hydroxylase domain proteins (PHD) and the CRL2VHL complex recognizes hydroxylated SETDB1 for ubiquitin-mediated degradation. Under hypoxic conditions, SETDB1 accumulates by escaping CRL2VHL activity. Loss of SETDB1 in hypoxia compared with that in normoxia escalates the production of transposable element (TE)-derived double-stranded RNAs (dsRNAs), thereby hyperactivating the immune-inflammatory response. In addition, strong derepression of TEs in hypoxic cells lacking SETDB1 triggers DNA damage-induced death. Our collective results support a molecular mechanism of oxygen-dependent SETDB1 degradation by the CRL2VHL E3 complex and reveal a role of SETDB1 in genome stability under hypoxia.

2024-01-26 | PXD037104 | Pride

Cellular and molecular characterization of the altered metabolism in RCC

Project description:RCC cells (786-O) were transfected with VHL. The parental cell line should be compared to the transfectant (+ VHL) under nomoxia as well as under hypoxia conditions. We want to distinct the VHL-mediated gene expression from the hypoxia-mediated and study the influence of both on the cellular metabolism. RNA of VHL-negative 786-O RCC cell line and VHL-transfectants incubated during normoxia and hypoxia conditions were analysed by cDNA microarray.

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Transcription profiling of C. elegans hypoxia responses

Project description:The goal of the study was to identify hypoxia-induced gene expression changes in C. elegans and to determine which of these responses to hypoxia were regulated by hif-1. Towards these aims, we analyzed mRNA expression patterns in synchronized populations of wild-type worms that were cultured in standard lab conditions (Snormoxia) or in hypoxia. We also assayed mRNA from two mutant strains: (i) animals carrying the strong loss-of-function mutation in hif-1 and (ii) C. elegans that carry a deletion in vhl-1 and express the HIF-1 protein at constitutively high levels. In the microarray experiments, 3 strains were assayed: wild type N2, hif-1 (ia04), and vhl-1 (ok161). Worms were incubated for 4 hours in 21% oxygen or 0.1% oxygen at 210C. Animals were quickly harvested in ice cold M9 buffer, and poly (A) RNA was isolated using established procedures. No more than 3 minutes elapsed between the removal of plates from the hypoxic chamber and the addition of Trizol. RNA was isolated from three independent experiments for each experimental condition (3 genotypes; normoxia vs hypoxia). mRNAs were hybridized to whole-genome microarrays which contained probes for 17,817 predicted genes (94% of the genome). Ch1 in the array reprents the data for the worms growed under hypoxia; and Ch2 in the array reprents the data for the worms growed under normoxia.

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RNA expression data from kidneys lacking von Hippel-Lindau (VHL) protein in tubular epithelial cells

Project description:The cellular response to low oxygen supply is mediated by hypoxia-inducible factors (HIF). Under hypoxic conditions, HIF is stabilized and target genes are induced. Under normoxia, however, HIF is ubiquitinated through the von Hippel-Lindau protein (VHL), which results in proteasomal degradation. HIF activation leads to induction of genes involved in erythropoiesis, angiogenesis, and cell survival. Furthermore, HIF orchestrates a metabolic shift from oxidative phosphorylation to glycolysis to facilitate ATP production under low oxygen conditions. We used microarrays to detail gene expression changes in kidneys with stable HIF activation in renal tubules, which was achieved by tubule-specific VHL ablation. Three week old Pax8-rtTA;LC-1;Vhl-floxed mice (n=4) and control littermates (n=4) were treated with doxycyline in drinking water for two weeks and put back on normal drinking water for one week. Six weeks old mice were sacrificed and kidneys harvested. Total RNA was extracted and hybridized on Affymetrix microarrays.

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RNA expression data from kidneys lacking von Hippel-Lindau (VHL) protein in tubular epithelial cells

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