Mitochondrial diseases: Exploring new treatment avenues
Mitochondrial diseases are a heterogeneous group of disorders which arise due to the dysfunction of mitochondria present in almost all cells except red blood cells of our body (RBCs are specially designed to support maximum transport of oxygen and acquire energy only through glycolysis and hence do not require mitochondria). These diseases can affect people of all age groups. As the primary function of mitochondria is to produce energy required for the cell to perform its activities, its failure makes a cell to act like a toy whose power supply has been cut. When the source of energy is cut, the body starts starving for energy. The frequency of these diseases is as high as 1 in every 5000 individuals. The effect of these diseases depends on the cells affected and the area to which they belong. For example, a single organ like eye might get affected leading to Leber hereditary optic neuropathy [LHON]) disease or multiple organs can be affected leading to more severe symptoms. The most pathetic truth about these diseases is that there is no direct cure for these disorders. Medications are used to just reduce the symptoms and to give temporary relief to the patients. However, current research is exploring new treatment avenues which can prevent and cure these diseases.
Structure of mitochondrion
What is a mitochondria and what is its function?
- Mitochondrion is the cell’s power house which utilizes the food (glucose, fats and proteins) to produce energy in the form of ATP in the presence of oxygen.
- On an average, each of our cells contains 500 to 2,000 mitochondria, each functioning as an energy factory fulfilling our energy needs.
- Preliminary digestion of glucose through glycolysis takes place in the cytoplasm. But the energy produced by glycolysis is not sufficient for higher organisms like human beings. Hence, the cells of higher organisms rely on the mitochondrion for their energy needs. Almost 90% of the cellular energy is produced by the mitochondria.
- Structurally, mitochondrion is divided into two chambers. The inner compartment is known as the matrix and contains mitochondrial DNA, transfer RNAs, enzymes and ribosomes. This is the main site for energy synthesis.
Steps through which energy is synthesized by the mitochondrion
- The three main steps involved in the energy synthesis by the mitochondrion are:
- The citric acid cycle occurring in the matrix of mitochondrion releases electron carriers in their reduced form (NADH and FADH2).
- The electron transport chain embedded in the inner mitochondrial membrane utilizes the energy of the electrons in NADH and FADH2 to pump protons (H+ ions) into the inter-membrane space.
- Finally, ATP synthesis takes place when energy produced by the backward flow of the protons into the matrix is utilized to attach inorganic phosphate to ADP to produce ATP.
Steps of energy synthesis
Origin of mitochondrial diseases
- Mitochondrial disease is usually a genetic inherited disorder which gets transmitted to the offspring when parents carry the mutated genes.
- In some rare situations, this diseases crops up even when parents are normal, due to some spontaneous mutations which occur prior to conception.
- Mitochondria contain two types of genetic material: mitochondrial DNA (mtDNA) and nuclear DNA.
- The inheritance pattern of mitochondrial disease is as follows:
- Maternal inheritance: When the mtDNA of mother is mutated, the abnormal gene gets transmitted to all of her children, as mtDNA is solely inherited from the mother. This kind of inheritance from mother is known as maternal inheritance. However, children might not be affected in the same manner as the degree of severity varies.
- Autosomal recessive inheritance: As nuclear DNA is inherited from both the parents, autosomal recessive mitochondrial disease arises when both parents carry the recessive form of the mutated gene. Both parents act as carriers of the disease and do not exhibit any symptom.
- Autosomal dominant inheritance: Autosomal dominant mitochondrial disease originates when any one parent has a dominant nuclear DNA gene mutation.
- Secondary disease: Mitochondrial function gets disturbed even due to faulty mutations taking place later in the life. These defective mutations can be an outcome of environmental factors like aging, consumption of alcohol, smoking, etc. However, mitochondrial disorders strictly refer to primary disorders discussed above.
Signs and symptoms of metabolic disorders
Infants with metabolic disorders usually show a delay or regression in development. Other symptoms depend largely upon the organ affected. For example, when muscles are affected weakness, cramping, muscle pain, opthalmoplegia and hypotonia (tension while stretching muscles) are observed. Optic neuropathy and retinitis pigmentosa leading to poor vision or blindness is observed when eyes get affected.
Clinical classification of the mitochondrial disorders
Depending upon the clinical features exhibited by the affected individuals, these disorders are classified into different clinical syndromes as follows:
- Kearns-Sayre syndrome (KSS)
- Alpers-Huttenlocher syndrome
- Chronic progressive external ophthalmoplegia (CPEO)
- Pearson syndrome
- Leigh syndrome (LS)
- Infantile myopathy and lactic acidosis
- Neurogenic weakness with ataxia and retinitis pigmentosa (NARP)
- Myoclonic epilepsy myopathy sensory ataxia (MEMSA)
- Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)
- Leber hereditary optic neuropathy (LHON)
Myoclonic epilepsy with ragged-red fibers (MERRF
Diagnosis or mitochondrial disorders
- Blood tests – Conducted to test the levels of lactate and pyruvate in blood
- Urine tests – Presence of organic acids in urine indicates metabolic problems.
- Muscle biopsy
- Genetic testing – conducted to study the types of genetic mutations
- Exercise and muscle strength testing – The strength and tolerance for physical activity are tested
Current treatment of mitochondrial diseases
- There is no cure for mitochondrial diseases. However, symptoms of the diseases are lessened to improve the quality of life and to limit further disability.
- Currently, patients are advised to stick to a particular diet plan as their caloric needs are different from the general population. For example, consumption of a snack made up of complex carbohydrate, high fat ketogenic diets are advised depending upon the person’s needs. Similarly, intake of iron in the form of supplements is also restricted as iron has a tendency to generate free radicals which poke holes in the mitochondrion.
- Exogenous administration of Coenzyme Q10 (lipophilic mobile electron carrier) is advised to many patients as its absence disrupts the flow of electron from one complex to another of the electron transport chain. Similarly, administration of a few amino acids like L-Arginine and Cysteine has been found to be effective in some study groups
- Patients are advised to quit alcohol and cigarette smoking as they hasten the progression of the diseases.
Research on FBXL4 gene
Research on TALENs
Current research to help people suffering from mitochondrial diseases
Currently, mutations in at least 100 genes have been linked to mitochondrial diseases. New gene mutations are being added to this list to enable more parents to discover the cause of their childrens' mitochondrial diseases. For example, the mutation in the nuclear gene FBXL4 is a very recent discovery (29 August 2013). This mutation affects the quantity of mitochondrial DNA and mitochondrial membrane potential, hence affecting the process of oxidative phosphorylation.
A breakthrough achievement in this line is the discovery of the mechanism through which mutated mitochondrial DNA (mtDNA) can be destroyed without affecting the normal mtDNA. TAL (transcription activator-like) effectors are the proteins naturally secreted by certain plant-infecting bacteria like Xanthomonas bacteria (infects various plant species like pepper, rice, citrus, cotton, tomato, and soybeans, etc). The DNA binding domain of this protein is fused with a DNA cleavage domain to create artificial restriction enzymes known as transcription activator-like effector nucleases (TALENs). A research group led by Carlos T. Moraes at University of Miami Miller School of Medicine designed mitochondrial-targeted TALENS (mitoTALENs) with a potency to bind and cut mitochondrial DNA. This mitoTALENs targeted a specific mutation in the gene Complex I, which causes the degenerative eye disease, Leber hereditary optic neuropathy (LHON).
Even though this research is still in its infancy, we never know when it can come up as ray of hope for many people suffering from mitochondrial diseases.
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