Genes provide the instructions for cells to function, and the NDUFA3 gene on chromosome 19 is one such example. It provides the blueprint for making a protein called NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 3. This protein is a component of the cellular machinery responsible for energy production. Its presence is necessary for this machinery to be built correctly and function as needed.
The Role in Cellular Energy Production
Within our cells are specialized compartments called mitochondria, often referred to as the cell’s powerhouses. Inside the mitochondria, energy from food is converted into a form the cell can use. This conversion happens along the mitochondrial inner membrane through a series of five protein complexes known as the electron transport chain. This chain works like an assembly line, passing electrons from one station to the next to generate power.
The first and largest station in this assembly line is called Complex I. Its job is to accept electrons from a molecule called NADH and start the energy conversion process. Complex I is a massive structure built from 45 different protein subunits. The protein created from the NDUFA3 gene is one of these subunits, specifically considered an accessory subunit.
While not directly involved in the primary chemical reactions of electron transfer, the NDUFA3 protein is required for the proper assembly and stability of Complex I. It is one of several subunits that join the structure during its formation, helping to build a part of the complex known as the matrix arm. Think of it as a specialized bolt in a large engine; without it, the engine cannot be fully assembled, and its performance is compromised.
Connection to Mitochondrial Complex I Deficiency
When the NDUFA3 gene has a mutation, it leads to the production of a faulty NDUFA3 protein. This defective protein cannot perform its role in the construction of Complex I. As a result, the Complex I structure may not form correctly or may be unstable, leading to a condition known as Mitochondrial Complex I deficiency. This is the most common disorder of the mitochondrial respiratory chain.
This deficiency means that the first step in the cellular energy assembly line is broken. The transfer of electrons from NADH is impaired, significantly reducing the cell’s ability to produce adenosine triphosphate (ATP). ATP is the molecule that serves as the main energy currency for all cellular activities.
Without sufficient ATP, cells cannot perform their normal functions, such as growth, repair, and communication. This breakdown at the molecular level leads to significant health problems, as the body’s tissues and organs are starved of the energy they need to operate.
Associated Health Conditions and Symptoms
The cellular energy shortage caused by NDUFA3-related Complex I deficiency does not affect all parts of the body equally. Tissues and organs with the highest energy demands are the most vulnerable. These include the brain, nerves, muscles, and heart, which are constantly active and require a continuous supply of ATP to function properly.
One of the most prominent diseases linked to NDUFA3 mutations is Leigh syndrome, a severe neurological disorder that typically appears in infancy. This condition is characterized by the progressive loss of mental and movement abilities and is caused by damage to the central nervous system.
Common clinical signs include muscle weakness (hypotonia), developmental delays, and seizures. Patients may also experience difficulty with movement (ataxia), vision problems, and issues with heart function. The specific presentation can vary, but the symptoms are often progressive and debilitating.
Research and Diagnostic Approaches
Investigating and diagnosing disorders related to the NDUFA3 gene involves a combination of scientific research and clinical methods. Scientists use genetic sequencing techniques, such as whole-exome sequencing, to read the genetic code of the NDUFA3 gene and identify specific mutations in affected individuals. This allows them to link a particular genetic flaw to the resulting disease.
For medical diagnosis, doctors start by evaluating a patient’s clinical symptoms, looking for characteristic signs like muscle weakness or developmental regression. Because mitochondrial disorders affect energy metabolism, physicians often run metabolic tests. These tests check for abnormal levels of certain substances in the blood or urine, such as elevated lactate, which can indicate that cellular energy production is not working correctly.
Sequencing the gene can pinpoint the exact mutation responsible for the faulty protein and the subsequent energy deficiency. In some cases, a muscle biopsy may be performed. This procedure involves taking a small sample of muscle tissue to directly measure the enzyme activity of Complex I, providing direct evidence of the mitochondrial dysfunction.