Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism

Dirckx, Naomi; Tower, Robert J.; Mercken, Evi M.; Vangoitsenhoven, Roman; Moreau-Triby, Caroline; Breugelmans, Tom; Nefyodova, Elena; Cardoen, Ruben; Mathieu, Chantal; Schueren, Bart Van der; Confavreux, Cyrille; Clemens, Thomas L.; Maes, Christa

doi:10.1172/jci97794

Cited by 76 publications

(99 citation statements)

References 48 publications

(89 reference statements)

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“…A similar trend in results were obtained using live cell imaging of the panel of RCC10 cells stained with the mitochondrial dyes MitoTracker red (Supplementary Figures 5B – E ) and MitoView green (Supplementary Figure 5F ), however the mitochondrial network analysis was not statistically significant (Supplementary Figure 5 ). Finally, consistent with a previous study ( 18 ), and other settings ( 40 ), we found no change in the expression of major regulators of mitochondrial biogenesis including PGC-1 α, PGC-1 β, NRF-1, NRF-2 (Supplementary Figures 6A – D ), while mtDNA copy number (Figure 4E and Supplementary Figure 6E ) and TFAM expression (Supplementary Figures 6F,G ) was increased upon pVHL re-expression. Taken together, these data indicate that pVHL regulated mitochondrial morphology correlates with changes in mitochondrial protein expression.…”

Section: Resultssupporting

confidence: 92%

VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function

et al. 2018

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Dysregulated mitochondrial function is associated with the pathology of a wide range of diseases including renal disease and cancer. Thus, investigating regulators of mitochondrial function is of particular interest. Previous work has shown that the von Hippel-Lindau tumor suppressor protein (pVHL) regulates mitochondrial biogenesis and respiratory chain function. pVHL is best known as an E3-ubiquitin ligase for the α-subunit of the hypoxia inducible factor (HIF) family of dimeric transcription factors. In normoxia, pVHL recognizes and binds hydroxylated HIF-α (HIF-1α and HIF-2α), targeting it for ubiquitination and proteasomal degradation. In this way, HIF transcriptional activity is tightly controlled at the level of HIF-α protein stability. At least 80% of clear cell renal carcinomas exhibit inactivation of the VHL gene, which leads to HIF-α protein stabilization and constitutive HIF activation. Constitutive HIF activation in renal carcinoma drives tumor progression and metastasis. Reconstitution of wild-type VHL protein (pVHL) in pVHL-defective renal carcinoma cells not only suppresses HIF activation and tumor growth, but also enhances mitochondrial respiratory chain function via mechanisms that are not fully elucidated. Here, we show that pVHL regulates mitochondrial function when re-expressed in pVHL-defective 786O and RCC10 renal carcinoma cells distinct from its regulation of HIF-α. Expression of CHCHD4, a key component of the disulphide relay system (DRS) involved in mitochondrial protein import within the intermembrane space (IMS) was elevated by pVHL re-expression alongside enhanced expression of respiratory chain subunits of complex I (NDUFB10) and complex IV (mtCO-2 and COX IV). These changes correlated with increased oxygen consumption rate (OCR) and dynamic changes in glucose and glutamine metabolism. Knockdown of HIF-2α also led to increased OCR, and elevated expression of CHCHD4, NDUFB10, and COXIV in 786O cells. Expression of pVHL mutant proteins (R200W, N78S, D126N, and S183L) that constitutively stabilize HIF-α but differentially promote glycolytic metabolism, were also found to differentially promote the pVHL-mediated mitochondrial phenotype. Parallel changes in mitochondrial morphology and the mitochondrial network were observed. Our study reveals a new role for pVHL in regulating CHCHD4 and mitochondrial function in renal carcinoma cells.

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Section: Resultssupporting

confidence: 92%

VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function

et al. 2018

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“…And inactivation of C. elegans VHL‐1 leads to the activation of HIF‐1, which induces the expression of genes that promote glycolysis, similar to what is observed in mammals . ATP levels in C. elegans vhl‐1 mutants have not yet been reported, but the upregulation of glycolytic enzymes in vhl‐1 mutants is likely to promote energy generation independently of mitochondria, as occurs in mammalian cells …”

Section: Is Increased Mitochondrial Fusion a Proxy For Increased Enermentioning

confidence: 68%

The Energy Maintenance Theory of Aging: Maintaining Energy Metabolism to Allow Longevity

Chaudhari

Kipreos

2018

BioEssays

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Fused, elongated mitochondria are more efficient in generating ATP than fragmented mitochondria. In diverse C. elegans longevity pathways, increased levels of fused mitochondria are associated with lifespan extension. Blocking mitochondrial fusion in these animals abolishes their extended longevity. The long-lived C. elegans vhl-1 mutant is an exception that does not have increased fused mitochondria, and is not dependent on fusion for longevity. Loss of mammalian VHL upregulates alternate energy generating pathways. This suggests that mitochondrial fusion facilitates longevity in C. elegans by increasing energy metabolism. In diverse animals, ATP levels broadly decreases with age. Substantial evidence supports the theory that increasing or maintaining energy metabolism promotes the survival of older animals. Increased ATP levels in older animals allow energy-intensive repair and homeostatic mechanisms such as proteostasis that act to prevent cellular aging. These observations support the emerging paradigm that maintaining energy metabolism promotes the survival of older animals.

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“…RANKL has recently been linked to mitochondrial mass in osteoclasts [17,43], and glucose uptake and glycolysis with increased PGC1α, GLUT1, LDHA, and VEGF expression in osteoblasts resembling the Warburg effect [44,45]. ERRα and Pgc1α, which is up-regulated in 4T1-ERRα-FP, are known to play a major role in coordinating oncometabolic programs [13].…”

Section: Discussionmentioning

confidence: 99%

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

et al. 2018

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Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-offunction analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1 mut carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases.

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Vhl deletion in osteoblasts boosts cellular glycolysis and improves global glucose metabolism

Cited by 76 publications

References 48 publications

VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function

VHL-Mediated Regulation of CHCHD4 and Mitochondrial Function

The Energy Maintenance Theory of Aging: Maintaining Energy Metabolism to Allow Longevity

ERRα promotes breast cancer cell dissemination to bone by increasing RANK expression in primary breast tumors

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