MT-ND5 gene

The MT-ND5 gene provides instructions for a key mitochondrial protein, and variants in this gene are associated with complex, overlapping mitochondrial disorders.

Normal Function

The MT-ND5 gene provides instructions for making a protein called NADH dehydrogenase 5. 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

Leigh syndrome

Variants in the MT-ND5 gene have been identified in a few people with Leigh syndrome. Children with this condition may experience vomiting, seizures, delayed development, muscle weakness, and problems with movement. Heart disease, kidney problems, and difficulty breathing can also occur. A few children with Leigh syndrome caused by MT-ND5 gene variants have had additional features, including slow growth before birth (intrauterine growth retardation) and distinctive facial features. These genetic changes disrupt the activity of complex I, impairing the ability of mitochondria to produce energy.

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes

Variants in the MT-ND5 gene are responsible for a small percentage of all cases of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This condition affects many of the body's systems, particularly the brain and nervous system (encephalo-) and muscles (myopathy).

• Most people with MELAS caused by MT-ND5 gene variants have the variant that replaces the nucleotide guanine with the nucleotide adenine at gene position 13513 (written as G13513A).
• These variants reduce the activity of complex I, disrupting energy production.
• Some individuals with MT-ND5 variants exhibit signs of MELAS in combination with other conditions, such as Leigh syndrome or Leber hereditary optic neuropathy.
• A few individuals have been reported with signs and symptoms of all three of these mitochondrial conditions.

It is unclear why changes in the MT-ND5 gene can cause such a large variety of signs and symptoms, and even within a single family, affected individuals may have different health problems caused by the same genetic change.