Fumarate hydratase (FH) is an enzyme found in human cells that plays a fundamental part in cellular metabolism. It manages a specific chemical reaction necessary for cellular energy production. The FH protein is produced from the FH gene and exists in two distinct locations within the cell. One form is situated in the mitochondria, the cell’s energy-producing compartments, while the other is found in the cytosol, the fluid-filled space outside the nucleus.
FH’s Essential Role in Cellular Energy Production
The primary function of the mitochondrial form of fumarate hydratase is its role within the tricarboxylic acid cycle (TCA cycle or Krebs cycle). This cycle is a series of chemical reactions that forms the final common pathway for the oxidation of carbohydrates, fats, and amino acids. Within the TCA cycle, FH catalyzes the reversible hydration of fumarate to L-malate, the seventh step in the eight-step cycle.
This conversion is a fundamental checkpoint for moving carbon atoms through the cycle to prepare for the final stage of energy production. The subsequent steps in the TCA cycle rely on L-malate to complete the loop and regenerate the starting molecule. The ultimate goal of these reactions is not to produce energy directly, but to generate reduced electron carriers, specifically NADH and FADH2.
These electron carriers then feed into the electron transport chain, where their energy is harvested to produce the vast majority of the cell’s adenosine triphosphate (ATP). The proper action of fumarate hydratase is necessary to ensure the continuous and efficient flow of electrons that power the cell. The cytosolic version of the enzyme also helps metabolize fumarate, a byproduct generated in other pathways, such as the urea cycle and amino acid catabolism.
When the FH gene is healthy, the enzyme maintains a delicate balance of molecules, ensuring that the TCA cycle operates without interruption. This allows the cell to efficiently use oxygen and convert fuel sources into the precursors needed for ATP synthesis. A functional FH enzyme is required to sustain the high energy demands of most tissues, particularly those with high metabolic rates.
Metabolic Consequences of Fumarate Hydratase Deficiency
A deficiency in fumarate hydratase activity, typically caused by a mutation in the FH gene, immediately disrupts the TCA cycle, leading to a profound metabolic imbalance. The most direct consequence is the cellular accumulation of the enzyme’s substrate, fumarate, which can rise to millimolar levels. Fumarate is referred to as an “oncometabolite” because its excessive buildup drives the initiation and progression of cancer.
The accumulated fumarate chemically inhibits a family of enzymes known as alpha-ketoglutarate-dependent dioxygenases. A particularly sensitive target is the prolyl hydroxylase (HPH) enzyme, which normally marks the Hypoxia-Inducible Factor-1\(\alpha\) (HIF-1\(\alpha\)) protein for destruction. Inhibiting HPH prevents the breakdown of HIF-1\(\alpha\).
This stabilization causes HIF-1\(\alpha\) to accumulate, activating genes typically only switched on when the cell is starved of oxygen. This leads to “pseudohypoxia,” where the cell behaves as if it is in a low-oxygen environment, even when oxygen levels are normal. The cellular response to this false alarm is a dramatic metabolic shift.
The cell begins to rely heavily on glycolysis, the pathway that breaks down glucose in the absence of oxygen, a phenomenon known as the Warburg effect. This shift directs energy production away from the highly efficient mitochondrial pathway and toward the less efficient cytosolic pathway. High levels of fumarate can also lead to the chemical modification of other cellular proteins, a process called succination, which further alters cell signaling and contributes to tumor development.
The Hereditary Cancer Syndrome Linked to FH Mutation
The inheritance of a germline mutation in the FH gene causes Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC syndrome). This condition is passed down in an autosomal dominant pattern, meaning a person needs only one altered copy of the gene to be at risk. Individuals with HLRCC have a 50% chance of passing the mutation to their children.
The syndrome is defined by a characteristic triad of tumors affecting the skin, uterus, and kidneys. Multiple cutaneous leiomyomas, which are benign tumors of the smooth muscle, typically develop on the skin, often presenting as painful bumps or nodules on the trunk and limbs. These tumors can be sensitive to cold or light touch, causing significant discomfort.
For women with HLRCC, the syndrome almost universally involves the development of uterine leiomyomas, commonly known as fibroids. These fibroids tend to be numerous, appear at an earlier age, and grow larger than those found in the general population. They often lead to symptoms that require surgical intervention, such as heavy menstrual bleeding and pain.
The most serious clinical manifestation of HLRCC is the increased risk for an aggressive form of kidney cancer, specifically type 2 papillary renal cell carcinoma. This cancer is often asymptomatic at its earliest stages and can grow and spread rapidly, resulting in a poor prognosis if not detected early. Genetic testing for the FH mutation is highly recommended for at-risk individuals to allow for proactive surveillance and early treatment.