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2024

Nature: Mitochondrial complex I promotes renal cell carcinoma metastasis

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Metabolic dysfunction is present in most renal cancers, but how this dysfunction affects cancer progression in humans is unclear.

On August 14, 2024, the Ralph J. DeBerardinis team at the University of Texas Southwestern Medical CenterNature Online publication entitled"Mitochondrial complex I promotes kidney cancer metastas"The research paper, the studyInjected in surgical tumor resection in more than 80 patients with kidney cancer¹³C- labeled nutrients.From [U-¹³C] The labeling of glucose varies by subtype, indicating that the renal environment alone does not explain all tumor metabolic reprogramming. Clear cell renal cell carcinoma (ccRCC) showed inhibitory labeling of tricarboxylic acid (TCA) cycle intermediates in both in vivo and in vitro organotypic cultures as compared to adjacent kidneys, suggesting that inhibitory labeling is tissue-intrinsic.

patient infusion [1,2-¹³C] acetate and [U-¹³C] glutamine, combined with respiration measurements of isolated human kidney and tumor mitochondria, showed reduced electron transport chain activity in ccRCC, contributing to reduced oxidation and enhanced reductive TCA cycle labeling. However, ccRCC transfer unexpectedly enhanced TCA cycle labeling compared to primary ccRCC, suggesting differences in the metabolic program during patient transfer. In mice, stimulation of respiration or NADH circulation in renal cancer cells was sufficient to promote metastasis, whereas inhibition of electron transport chain complex I reduced metastasis.These findings in humans and mice suggest that metabolic properties and loads change during the progression of kidney cancer, and that mitochondrial function limits metastasis rather than growth at the primary site.

Mitochondrial alterations are a common feature of renal cell carcinoma (RCC), but the mechanisms of mitochondrial abnormalities vary by RCC subtype.Clear cell RCC (ccRCC) is the most common form of RCC, with approximately 90% of tumors having biallelic inactivation of the gene encoding the tumor suppressor von Hippel-Lindau (VHL). Deletion of VHL results in pseudo-hypoxic stabilization of the HIF alpha subunit and chronic activation of HIF target genes, many of which promote glycolysis and inhibit glucose oxidation.

A fraction of chromophobe (chromophobe) RCCs contain mutations in electron transport chain (ETC) complex ITumorigenic cells (oncocytomas) accumulate defective mitochondria through somatic mutation of complex I and impaired mitochondrial elimination programs. Pathogenic defects in the metabolic enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDH) are also initiating events in some renal cancers.These data suggest that many RCCs selectively reduce mitochondrial metabolism during initiation and growth in the kidney.

Although there is genetic evidence of mitochondrial dysfunction, it is not clear how these mutations affect the vegetative metabolism of human RCC in vivo.Intraoperative infusion¹³C- labeled nutrients, and analysis of metabolites extracted from surgical excision samples¹³C markers, which can reveal metabolic differences between tumors and adjacent tissues or between tumors in different patients. It was previously reported that the glucose carbon contribution to TCA cycle intermediates was suppressed in five human ccRCCs, implying reduced glucose oxidation in these tumors.We explored why this phenotype occurs, whether it is often a feature of primary renal tumors, and how metabolic properties evolve during ccRCC progression to metastatic disease.

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