Posted on June 11, 2019 at 1:00 AM
Mitochondrial diseases occur when mitochondria do not function properly or fail to function at all. Mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support organ function. When mitochondrial function is disrupted, less and less energy is produced within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole organ systems begin to fail.
The parts of the body that require the greatest amounts of energy, such as the heart, brain, muscles and lungs, are the most affected by mitochondrial diseases. These diseases are typically difficult to diagnose because they can affect each individual differently. Symptoms can include seizures, strokes, severe developmental delay, and the inability to walk, talk, see, and digest food combined with an assortment of other complications. If three or more organ systems are involved, mitochondrial disease should be suspected.
For the Scientist: Mitochondrial diseases are caused by either inherited or spontaneous mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA), which lead to altered functions of the proteins or RNA molecules that normally reside in mitochondria. Problems with mitochondrial function, however, may only affect certain tissues due to factors present during development and growth. These factors are not currently known. Even when considering tissue-specific isoforms of mitochondrial proteins, it is difficult to explain the variable patterns of affected organ systems in the mitochondrial syndromes that are seen clinically.
Because mitochondria have so many diverse functions in various tissues, there are hundreds of different mitochondrial diseases. Each disorder produces a spectrum of abnormalities that can be confusing to both patients and physicians in the early stages of diagnosis. A complex interplay between hundreds of genes and cells must occur to keep our metabolic machinery running smoothly, and it is a hallmark of mitochondrial diseases that identical mtDNA mutations may not produce identical diseases. Genocopies are diseases that are caused by the same mutation but may not look the same clinically.
The converse is also true: different mutations in mtDNA and nDNA can lead to the same diseases, known as phenocopies. A good example is Leigh syndrome, which can be caused by about a dozen different gene defects. This syndrome is characterized by bilaterally symmetrical MRI abnormalities in the brain stem, cerebellum, and basal ganglia, often accompanied by elevated lactic acid levels in the blood or cerebrospinal fluid. It may be caused by the NARP mutation, the MERRF mutation, complex I deficiency, cytochrome oxidase (COX) deficiency, pyruvate dehydrogenase (PDH) deficiency, and other unmapped DNA changes. However, not all children with these DNA abnormalities will go on to develop Leigh syndrome.
Mitochondrial diseases are even more complex in adults because detectable changes in mtDNA occur as we age and, conversely, the aging process itself may result from deteriorating mitochondrial function. There is a broad spectrum of metabolic, inherited and acquired diseases in adults in which abnormal mitochondrial function has been postulated or demonstrated.