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Mutations in Mitochondrial DNA Underlie Certain Subtype of Aggressive Renal Cancer

NEW YORK – A team led by researchers at the National Cancer Institute has found that an increase in mutations in mitochondrial DNA (mtDNA) is responsible for promoting a cellular metabolic shift which underlies hereditary leiomyomatosis and renal cell carcinoma (HLRCC), an aggressive form of kidney cancer.

In a paper published on Tuesday in Science Signaling, the researchers noted that defining the metabolic basis of cancer begins with understanding the mechanisms of the Warburg shift, which is a form of cellular metabolism found in cancer cells that tends to increase lactate fermentation even in the presence of oxygen — this process is called aerobic glycolysis.

According to the study's senior author and NCI researcher Marston Linehan, HLRCC is a familial cancer syndrome "in which affected individuals are at risk for the development of cutaneous and uterine leiomyoma and an aggressive form of renal cell carcinoma that has a propensity to spread when the tumors are small." The disease is caused by a germline mutation of fumarate hydratase (FH), the gene for the Krebs cycle enzyme, and FH-deficient RCC is characterized by a Warburg metabolic shift to aerobic glycolysis and rapid metastasis, he added.

In their study, the researchers said they observed impairment of the mitochondrial respiratory chain in tumors from HLRCC patients. When they conducted biochemical and transcriptomic analyses, they further found that respiratory chain dysfunction in the tumors was due to loss of expression of mtDNA-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations.

"We showed that accumulation of fumarate in HLRCC tumors inactivated the critical factors responsible for replication and proofreading of mitochondrial DNA, thereby resulting in a metabolic shift to aerobic glycolysis and a diversion of glucose to the pentose phosphate pathway (PPP)," Linehan said. "The PPP is a main source of cytosolic [nicotinamide adenine dinucleotide phosphate] NADPH, which is critical for the metabolic steps leading to fatty acid synthesis, a major rate-limiting pathway in cancer."

The researchers evaluated the metabolic and biochemical phenotype of FH-deficient renal cancer in human tumors and tumor-derived cell lines. They found that both the mutations and the loss of mtDNA that they observed in FH-deficient tumors were associated with fumarate-mediated covalent modification of the mtDNA replicative machinery, including polymerase gamma (POLG), the sole mtDNA polymerase, which is responsible for replication and proofreading of mtDNA.

This suggested that a defining feature of FH-deficient renal cancers is the inactivation of mtDNA maintenance and repair proteins, caused directly by elevated fumarate levels, leading to loss of respiration and an early, irreversible shift to aerobic glycolysis.

When they looked at HLRCC tumor-derived cell lines, which represented a homogeneous FH-/- model because the stromal and immune cells of the tumor were excluded, the researchers found variable degrees of mtDNA aberrations, ranging from various missense mutations that disabled mitochondrial-encoded respiratory chain components, to the complete loss of the mitochondrial genome. They concluded that the loss of mitochondrial respiration in FH-/- cells was irreversible, because re-expression of FH did not restore respiration despite restoration of POLG activity in an environment that no longer contained elevated fumarate levels.

The mitochondrial dysfunction forces metabolic remodeling in HLRCC tumors that favors anabolic pathways offering bioenergetic and biosynthetic advantages that tumors need for growth and metastasis, the researchers concluded.

"This study defines the basis for early detection of metastatic HLRCC-associated cancer with 18FDG-PET metabolic imaging, as well as provides the foundation for the development to therapeutic approaches for this and other cancers characterized by a Warburg metabolic shift to aerobic glycolysis," Linehan said.