NADK2

NADK2 is a mitochondrial enzyme that generates NADP⁺, a critical cofactor for redox balance, fatty acid oxidation, and biosynthetic pathways inside mitochondria.

Mutations in the NADK2 gene can impair mitochondrial metabolism, leading to rare but severe neurometabolic disorders and emerging links to cancer, fibrosis, and age-related diseases.

What is NADK2 (NAD Kinase 2, Mitochondrial)?

The NADK2 gene encodes mitochondrial NAD kinase 2, an enzyme critical for maintaining the mitochondrial pool of NADP⁺ and NADPH. These cofactors are essential for mitochondrial redox balance, energy metabolism, and biosynthetic processes.

The NADK2 Gene and Encoded Protein

Located on chromosome 5p13.2, NADK2 produces a 442-amino acid protein localized to the mitochondrial matrix. This protein functions as a homodimer and catalyzes the phosphorylation of NAD⁺ (and, to a much lesser extent, NADH) using ATP or inorganic polyphosphate as a phosphate donor.

Key Enzymatic Function

NADK2 catalyzes the reaction:

NAD⁺ + ATP → NADP⁺ + ADP + H⁺

This reaction is the sole source of mitochondrial NADP⁺, a cofactor required for:

• Fatty acid oxidation
• Lysine and proline metabolism
• Redox regulation through NADPH-dependent antioxidant systems (e.g., glutathione, thioredoxin)
• Biosynthesis of collagen and other macromolecules

Importance of NADP⁺ in Mitochondria

NADP⁺ is central to mitochondrial metabolism. It fuels several enzymatic reactions and protects cells from oxidative damage by supporting the regeneration of antioxidant systems. 

Because the mitochondrial NADP(H) pool is compartmentalized and cannot be replenished from the cytosol, NADK2 is essential for mitochondrial function.

When is NADK2 Testing or Research Relevant?

NADK2 testing may  be relevant in the following scenarios:

Research on Metabolic Disorders and Related Conditions

NADK2 has been the subject of growing research interest due to its involvement in rare mitochondrial and metabolic disorders. 

While not commonly used in routine clinical testing, it is important in research contexts, particularly in investigating 2,4-Dienoyl-CoA Reductase Deficiency.

2,4-Dienoyl-CoA Reductase Deficiency (DECRD)

2,4-Dienoyl-CoA reductase deficiency (DECRD or DE-RED) is an extremely rare genetic condition caused by changes (mutations) in the NADK2 gene. This gene helps make an enzyme in the mitochondria that breaks down certain fats for energy. 

Without it, the body can't properly use unsaturated fats, leading to a buildup of harmful substances and insufficient energy for proper growth and function.

Symptoms

Only three cases have been reported. In these, symptoms started at birth and included:

• Poor feeding and frequent vomiting
• Small head and body size (microcephaly)
• Weak muscle tone (hypotonia)
• Trouble gaining weight
• Breathing issues, seizures, and unusual eye movements (nystagmus)

Diagnosis

Newborn screening may show high levels of C10:2 acylcarnitine in the baby’s blood. If results are abnormal, more tests, such as bloodwork, urine tests, or genetic testing, are needed to confirm the diagnosis.

Inheritance

DECRD is inherited in an autosomal recessive pattern. To have the condition, a baby must get one non-working copy of the NADK2 gene from each parent. Parents are usually healthy carriers without symptoms.

Treatment

Because so few cases exist, there's limited information on treatment. Reported approaches include:

• A special formula low in lysine (an amino acid)
• Carnitine supplements to help support fat metabolism

Early diagnosis and careful management can help reduce complications.

Broader Mitochondrial Dysfunction

NADK2 deficiency impairs enzymes that rely on NADPH, contributing to neurodevelopmental delay, optic atrophy, muscle weakness, and metabolic crises

Emerging Research

• Cancer: Altered NADK2 expression has been observed in hepatocellular carcinoma and IDH2-mutant cancers
• Fibrosis: Higher NADK2 expression may contribute to collagen overproduction in fibrotic diseases like idiopathic pulmonary fibrosis (IPF)
• Neurodegenerative conditions and metabolic aging: Still under investigation

Limited Current Clinical Testing

At this time, NADK2 is not part of standard clinical panels. However, whole exome sequencing or targeted genetic testing may be used in suspected mitochondrial or fatty acid oxidation disorders. Research-grade assays can assess its expression or function in experimental settings.

NADK2 Genetic Testing: Test Procedure and Interpretation

Testing for NADK2 is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for NADK2 genetic testing are considered to be without mutations that can alter the activity of the NADK2 proteins.

What Do Mutations in NADK2 Mean?

Mutations in NADK2 impair its kinase activity, leading to depleted NADP⁺ and NADPH in mitochondria. This can result in:

• Impaired fatty acid and lysine degradation
• Disrupted proline synthesis (due to loss of NADPH-dependent P5CS activity)
• Decreased collagen production in connective tissues
• Altered redox balance and increased susceptibility to oxidative damage

Clinical Manifestations of NADK2-Related Disorders

In patients with 2,4-dienoyl-CoA reductase deficiency (DECRD), NADK2 mutations may cause:

• Failure to thrive
• Developmental delay and hypotonia
• Optic atrophy
• Seizures and microcephaly
• Hyperlysinemia and lactic acidosis

Notable Pathogenic Variants

• R340X: Severe early-onset phenotype
• c.956+6T>C: Affects RNA splicing, leads to protein truncation
• M1V (start-loss): Results in cytosolic mislocalization and reduced enzymatic function

Functional Insights

• Knockout models show increased reactive oxygen species (ROS), neuromuscular degeneration, and proline auxotrophy
• Liver-specific knockouts develop hepatic steatosis and oxidative stress
• Functional rescue is possible in vitro with wild-type NADK2 or NAD⁺ precursor supplementation

What Does the Absence of Studied NADK2 Variants Mean?

A negative NADK2 test does not rule out mitochondrial disease or redox imbalance. Other genes in the NADPH-producing or fatty acid oxidation pathways may contribute to the phenotype.

Limited Interpretability of Isolated Negative Results

A negative NADK2 genetic result may not provide actionable diagnostic information without a strong clinical indication (e.g., hyperlysinemia, optic atrophy, metabolic acidosis). Interpretation should consider the broader clinical context and, when appropriate, functional testing.

Clinical Takeaways

NADK2 is essential for mitochondrial NADPH production, impacting energy metabolism, redox balance, and biosynthesis.

Mutations can cause severe mitochondrial disorders but may also present as milder neurometabolic or fibrotic phenotypes.

NADK2 testing should be considered in infants or children with unexplained metabolic encephalopathy, hyperlysinemia, or optic atrophy.

Emerging therapies include NAD⁺ precursors (e.g., nicotinamide riboside) to restore mitochondrial redox function.

High NADK2 expression may be a biomarker in diseases involving excessive collagen production.

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