MT-ND4 gene

The MT-ND4 gene encodes a protein critical for mitochondrial energy production, with specific variants linked to inherited vision loss and progressive brain disorders.

Normal Function

The MT-ND4 gene provides instructions for making a protein called NADH dehydrogenase 4. This protein is part of a large enzyme complex known as complex I, which is active in mitochondria. Mitochondria are structures within cells that convert the energy from food into a form that cells can use through a process called oxidative phosphorylation, which uses oxygen and simple sugars to create adenosine triphosphate (ATP), the cell's main energy source.

Complex I is one of several enzyme complexes necessary for oxidative phosphorylation. Within mitochondria, these complexes are embedded in a tightly folded, specialized membrane called the inner mitochondrial membrane. During oxidative phosphorylation, mitochondrial enzyme complexes carry out chemical reactions that drive the production of ATP. Specifically, they create an unequal electrical charge on either side of the inner mitochondrial membrane through a step-by-step transfer of negatively charged particles called electrons. This difference in electrical charge provides the energy for ATP production.

Complex I is responsible for the first step in the electron transport process, the transfer of electrons from a molecule called NADH to another molecule called ubiquinone. Electrons are then passed from ubiquinone through several other enzyme complexes to provide energy for the generation of ATP.

Health Conditions Related to Genetic Changes

Leber hereditary optic neuropathy

Several variants (also called mutations) in the MT-ND4 gene are known to cause Leber hereditary optic neuropathy, an inherited form of vision loss. Each of these variants changes a single protein building block (amino acid) in the NADH dehydrogenase 4 protein.

• One MT-ND4 gene variant is the most common cause of Leber hereditary optic neuropathy, responsible for about 70 percent of all cases worldwide.
• This variant, written as G11778A or Arg340His, replaces the amino acid arginine with the amino acid histidine at protein position 340.
• This variant tends to cause severe vision loss, with little chance of recovery.

These genetic changes appear to prevent complex I from interacting normally with ubiquinone, which may affect the generation of ATP. MT-ND4 gene variants may also increase the production within mitochondria of potentially harmful molecules called reactive oxygen species. It remains unclear why the effects of these variants are often limited to the optic nerve.

Leigh syndrome

A variant in the MT-ND4 gene has been identified in a small number of people with Leigh syndrome, a progressive brain disorder that typically appears in infancy or early childhood. Affected children may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur.

The MT-ND4 variant associated with Leigh syndrome, written as C11777A or Arg340Ser, replaces the amino acid arginine with the amino acid serine at protein position 340. This genetic change appears to disrupt the normal function of complex I in mitochondria.