Mitochondria are organelles present in every cell of the human body except red blood cells. Mitochondria are responsible for generating more than 90 % of the energy the human body needs to sustain life and support life activities. When the respiratory chain of the mitochondria is dysfunctional, the energy produced in the mitochondria becomes less and less, which then consumes the energy of the cells, resulting in cell damage and even cell death. Without healthy mitochondria, cells cannot function properly.
The failure caused by mitochondrial dysfunction is the main cause of mitochondrial disease because mitochondria is a unique organelle, which carries genetic material. However, it is well known that there are four epigenetic regulation modes between nuclear genes and mitochondrial genes: (1) the epigenetic mechanism regulating nuclear gene expression can affect mitochondria by regulating the expression of nuclear-encoded mitochondrial genes. (2) the methylation pattern of nuclear genes is determined by cell-specific mitochondrial DNA content and mitochondrial activity. (3) MtDNA mutation affects the nuclear gene expression pattern and nuclear DNA (ncDNA) methylation level. (4) MtDNA itself is also modified by epigenetics. Therefore, fundamentally, mitochondrial diseases are not only affected by mitochondrial DNA mutations but also caused by mutations in ncDNA.
This special and complex pathogenesis determines the difficulty of diagnosis and treatment of mitochondrial diseases. Due to the high demand for energy from the brain and muscles, once the mitochondria become dysfunctional, it is bound to affect the brain and muscles of the body, leading to cerebrospinal disease. Besides, other organs are often affected by mitochondrial diseases, including eyes, ears, heart, gastrointestinal tract, liver, kidneys, endocrine organs (such as thyroid and insulin-producing cells in the pancreas), and blood, depending on the affected cells. Because the symptoms of mitochondrial disease are usually similar to those of other serious diseases, it can make the disease difficult to diagnose.
It is clear that mitochondrial disease is challenging because it is probably the most diverse human disease at all clinical, biochemical, and genetic levels.
Some mitochondrial diseases affect only a single organ, but most mitochondrial diseases affect multiple organs and tissues of the human body and usually show obvious characteristics of neuromuscular disease. Mitochondrial disease can occur at any age. Many patients with mtDNA mutations present with the clinical syndrome, such as Kearns-Sayre syndrome (KSS). However, in other mitochondrial diseases, because of their widespread clinical heterogeneity, many patients can not be classified as suffering from a specific class of diseases, characterized by multiple clinical symptoms.
Any organ or system in the body can be affected by mitochondrial diseases, including the brain, heart and lungs, liver and intestines, and skin. For example, people with mitochondrial disease may have epilepsy and may have symptoms such as fatigue, vision and hearing loss, cognitive impairment, respiratory problems, or poor growth. Although the severity varies, generally speaking, mitochondrial disease is usually a crippling disease.
In some cases, these symptoms and signs may indicate a specific type of mitochondrial disease. Physical examinations must be performed to characterize the impact of various organs and to make a correct diagnosis. Laboratory studies usually include blood tests, brain MRI or CT scans, heart tests (electrocardiogram and echocardiography), ophthalmic and neurological assessments, and hearing tests. The increase of lactic acid or the ratio of lactic acid to pyruvate in blood or cerebrospinal fluid (> 20:1) is a common symptom of mitochondrial dysfunction. Muscle biopsies are the gold standard for the diagnosis of many mitochondrial diseases and require specialized microscopic analysis and biochemical tests (for example, measurement of enzyme activity in the mitochondrial respiratory chain). Finally, genetic tests are performed in blood, urine, or muscle tissue to identify the exact mutation that causes a particular mitochondrial disease.
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