Metabolic Reprogramming in Renal Cell Carcinoma

Renal cell carcinoma (RCC) exemplifies how oncogenic mutations, notably in the von Hippel-Lindau (VHL) gene, drive profound alterations in cellular metabolism. Loss of VHL stabilises hypoxia-inducible factors (HIFs), promoting a shift from mitochondrial oxidative phosphorylation to aerobic glycolysis, a phenomenon often termed the Warburg effect. Concurrently, clear cell RCC displays suppressed tricarboxylic acid (TCA) cycle flux and enhanced reliance on alternative substrates such as glutamine, which fuels reductive carboxylation and lipid synthesis. As tumours progress, particularly during metastasis, mitochondrial electron transport chain activity may be re-engaged to meet new energetic and biosynthetic demands. Beyond cancer cells, diverse stromal and immune populations within the tumour microenvironment adopt distinct metabolic states, from glycolytic immunosuppressive macrophages to exhausted T cells with impaired fatty acid oxidation. Understanding this dynamic metabolic landscape has unveiled vulnerabilities that can be exploited for diagnostics, prognostics and targeted therapies in RCC.

Research from Nature Portfolio

Recent studies have revealed that mitochondrial complex I activity is markedly reduced in primary clear cell carcinomas compared with adjacent normal kidney, leading to a preferential reductive mode of the TCA cycle in tumour cells. Paradoxically, metastatic lesions recover complex I function and oxidative labelling, pinpointing a metabolic switch essential for dissemination. Experimental modulation of electron transport chain activity can either inhibit or promote metastasis, identifying complex I as a candidate therapeutic target. Complementing these insights, nuclear magnetic resonance metabolomics of patient urine samples has defined a 32-metabolite signature that robustly discriminates RCC from controls, establishing a systematic workflow for non-invasive biomarker discovery.

Metabolic Reprogramming in Renal Cell Carcinoma publication trend

The graph below shows the total number of articles in metabolic reprogramming in renal cell carcinoma across all publications each year (not limited to Nature Index journals).

Technical terms

Glycolysis: Metabolic pathway converting glucose to pyruvate with net ATP production under aerobic or anaerobic conditions.

Tricarboxylic acid (TCA) cycle: Central mitochondrial pathway oxidising acetyl-CoA to generate reducing equivalents for ATP synthesis.

Oxidative phosphorylation: Process in which mitochondrial electron transport chains use reducing equivalents to generate a proton gradient that drives ATP production.

Reductive carboxylation: Reverse enzymatic reaction in which glutamine-derived α-ketoglutarate is converted to citrate under conditions of impaired respiration.

Hypoxia-inducible factors (HIF): Transcription factors stabilised by low oxygen or VHL loss, upregulating glycolysis, angiogenesis and survival pathways.

Tumour microenvironment: The complex ecosystem of cancer cells, stromal cells and immune cells interacting biochemically and spatially within a tumour.

References

1. Mitochondrial complex I promotes kidney cancer metastasis. Nature (2024).
2. Serum and Urine Metabolic Fingerprints Characterize Renal Cell Carcinoma for Classification, Early Diagnosis, and Prognosis. Advanced Science (2024).
3. VHL-deficiency leads to reductive stress in renal cells. Free Radical Biology and Medicine (2023).
4. Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics. Journal of Translational Medicine (2024).
5. Nuclear Magnetic Resonance metabolomics reveals an excretory metabolic signature of renal cell carcinoma. Scientific Reports (2016).