Primary Mitochondrial Diseases (PMDs) are a group of conditions that usually affect multiple organs and systems in the body. They are caused by problems in the mitochondria—the parts of our cells that produce energy. Specifically, the problem lies in a process called oxidative phosphorylation (OXPHOS), which is the final step in how cells make energy. This process takes place inside the inner membrane of mitochondria.
More than 300 different genetic changes(mutations) in both nuclear DNA (in the cell nucleus) and mitochondrial DNA (in the mitochondria) can interfere with this energy-making process. One of the most common mutations is called m.3243A>G, found in the MT-TL1 gene.This gene normally helps build transfer RNA for the amino acid leucine, which is needed to make mitochondrial proteins. The m.3243A>G mutation changes oneDNA letter (from A to G) at position 3243. This small change leads to mistakes in making proteins inside the mitochondria, resulting in faulty proteins that can’t do their job properly. This mainly affects Complex I, a key part of the OXPHOS system, which is responsible for electron transport and energy production. When Complex I is not working correctly, cells can’t manage energy and oxygen properly, leading to stress and damage.
This mutation was first found in people with a condition called classic MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes). Because of this, it has often been called the “MELAS mutation.” However, only about 5–10% of people with the m.3243A>G mutation actually have classic MELAS.
Most people with this mutation show other symptoms and fall into different categories:
Because of this wide range of symptoms, we recommend using the term m.3243A>G Primary Mitochondrial Disease instead of calling it the MELAS mutation. This name better reflects the diversity of conditions linked to this genetic change.
