Mitochondrial Medicine: Mitochondrial Metabolism, Diseases, Diagnosis and Therapy

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These defects include excessive oxidative stress and decreased energy supply to affected cells of the eye, particularly in the retina. Stealth notes that the science underlying Bendavia and Ocuvia is supported by more than independent, peer-reviewed publications and abstracts, and that these mitochondrial-targeted candidates represent a novel therapeutic approach to address a wide variety of diseases having unmet treatment needs including orphan mitochondrial diseases and mitochondrial medicine.

Novato, California based Raptor Pharmaceutical Corp. On Monday, August 17, Raptor announced that it has received U. Treatment of inherited mitochondrial diseases with cysteamine is potentially based on different mechanisms of action than that for treatment of cystinosis, although Raptor says one key biochemical reaction, which is the basis for the treatment of cystinosis, seems to play a significant role also. Cysteamine is an aminothiol that participates in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteine-cysteamine mixed disulfide. This cysteine-cysteamine mixed disulfide can exit the lysosome through the lysosome membrane as it is transported through the intestinal barrier or the blood brain barrier, by the lysine transporter or a lysine-like transporter, the PQLC2 protein.

Mitochondrial Medicine – Cardiomyopathy Caused by Defective Oxidative Phosphorylation

This biochemical reaction results in an increase of the cellular thiol pool, making more cysteine available for glutathione GSH synthesis. Glutathione is composed of the amino acids cysteine, glutamate and glycine. Availability of cysteine, which exists primarily as cystine, is the major rate-limiting factor in GSH production.

Leigh syndrome is a severe neurological disorder caused by genetic defects in mitochondrial or nuclear DNA affecting respiratory chain function that typically results in death within the first decade of life. The condition causes increased production of reactive oxygen species which disrupts mitochondrial electron transport and affects cellular function in a variety of tissues. Typically observed during the first year of life, Leigh syndrome is characterized by a failure to thrive, lack of coordination, involuntary and sustained muscle contraction, muscle wasting, and multiple organ failure.

The incidence of Leigh syndrome in the U. Cohen, M. These reactive oxygen species are abnormally high in patients with Leigh syndrome. In addition to providing an antioxidant activity directly, RP is believed to increase mitochondrial glutathione which acts as a scavenging agent of reactive oxygen species.


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Reactive oxygen species are a byproduct of mitochondrial energy production and place oxidative stress on cells. In patients with mitochondrial dysfunction, these reactive oxygen species are produced at dangerously high levels. By increasing levels of the antioxidant glutathione in the mitochondria, RP may reduce the toxic oxidative stress typically associated with mitochondrial disorders. Dear Colleagues: I would like to know if this new drug Raxone, can be useful in treatment of Kearn-Sayre sindrom?

Best regards Francisco Iberico Nogueira M. Mitochondrial disease can cause a vast array of health concerns, including fatigue, weakness, metabolic strokes, seizures, cardiomyopathy, arrhythmias, developmental or cognitive disabilities, diabetes mellitus, impairment of hearing, vision, growth, liver, gastrointestinal, or kidney function, and more.

These symptoms can present at any age from infancy up until late adulthood. Every 30 minutes, a child is born who will develop a mitochondrial disorder by age Overall, approximately 1 in every 4, individuals in the United States has a mitochondrial disease.

Demystifying Medicine 2013 - The Mitochondrion and Its Diseases

Given the various potential presentations that may occur, mitochondrial disease can be difficult to diagnosis and is often misdiagnosed. There are various methods to examine if an individual has mitochondrial disease. These include genetic diagnostic testing, genetic or biochemical tests in affected tissues, such as muscle or liver, and other blood or urine based biochemical markers. However, our knowledge is still growing and we do not yet know all of the genes that could potentially cause mitochondrial disease.

Environmental toxins can also trigger mitochondrial disease. Currently there is no highly effective treatment or cure for mitochondrial disorder. Both in cybrid lines as well as in vivo in mice this approach has been shown to be successful [ 77 ]. In mice the REs shifted the heteroplasmy grade in liver and skeletal muscle, without causing mtDNA depletion [ 78 ]. Peptide nucleic acid oligomers. Peptide nucleic acid oligomers are nucleic acid analogues, similar to oligodeoxynucleotides in that they retain the ability to base pair via standard Watson—Crick interactions, that selectively bind to complementary DNA or RNA sequences with a very high affinity.

Despite that it has been shown possible to introduce these agents into mitochondria they did not affect the heteroplasmy level [ 80 ].

Further results of studies are necessary to judge the potential of this approach. Satellite cells. Skeletal muscle satellite cells are quiescent mononucleated myogenic cells, located between the sarcolemma and basement membrane of terminally differentiated muscle fibres [ 81 ].

These cells are potent to respond to myotrauma by proliferation, differentiating to new myofibers, fusing with existing muscle fibers and thereby repairing damaged fibers. Strikingly, satellite cells in culture of a sporadic patient with a heteroplasmic tRNA mutation did not harbour the mutation [ 83 ].

Shoubridge postulated that the most likely mechanism to explain the loss of mutant DNA in lineages of the dividing satellite cells in sporadic cases is random genetic drift. Both chemically induced myotrauma and resistance exercise have been evaluated for this purpose. It is not expected that this form of treatment will ever reach clinical practice though from a basic concept point of view alternatives, like resistance training, might do.

Twelve weeks of progressive overload leg resistance training in patients with single, large scale deletions of mtDNA led to increased muscle strength, myofibre damage and regeneration, increased proportion of satellite cells and improved muscle oxidative capacity.

Exercise training. Exercise intolerance is a major problem in patients with mitochondrial disease. This affects the quality of life and, due to deconditioning, may result in inverse adaptations, deteriorating the exercise tolerance even more [ 87 ]. Increased work load and oxidative capacity were observed, but no change in mutation load in muscle after exercise. Both studies show that aerobic exercise training has beneficial effects but, in contrast to resistance training, did not alter the mutation load in skeletal muscle.

Sirtuins are an evolutionarily conserved class of proteins that regulate a variety of cellular functions such as genome maintenance, longevity, and metabolism [ 93 ]. Seven human sirtuins SIRT1—7 are presently known.

The therapeutic potential of SIRT1 has been explored in a variety of diseases, including mitochondrial disease [ 93 ]. Mice treated with resveratrol have increased SIRT1 protein levels, thereby upregulating mitochondrial number and function and improving motor function [ 94 ]. Also a significantly increase in aerobic capacity, as shown by an increased running time and oxygen consumption in muscle fibers, was observed [ 22 ].

Resveratrol also maintained redox environment and reduced oxidative stress in reperfusion injury [ 95 ]. Both approaches benefited the COX10 mutant animals, resulting in a longer life span and delayed onset of the myopathy.

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The likely mode of action of this approach is induction of mitochondrial biogenesis and thereby optimizing the residual complex IV activity. Metabolic manipulation can be defined as the use of dietary modification or small molecule therapy to compensate for a deranged biological process [ 97 ].

Mitochondrial Diseases

In case of mitochondrial dysfunction, examples hereof are preventing oxygen damage by scavenging enzymes or compounds restoring disturbed mitochondrial calcium metabolism by small molecules interfering with mitochondrial calcium transport. In fact also the use of dietary compounds to modulate transcription as described above, belong to this class of interventions. Nutritional intervention. Mitochondrial function is influenced by nutrition. They found biochemical improvement in the mitochondrial function in seven out of 10 patients following intervention.

Establishing a Diagnosis as soon as Possible

Preventing oxidative damage. Consequently, damage of intracellular structures by oxidizing proteins and DNA may happen [ 11 ]. Fortunately, cells are equipped with an efficient ROS scavenging machinery, including enzymes like SOD and vitamins like tocopherols [ 98 ]. Mice incapable of reducing superoxide die shortly after birth, with severe metabolic and mitochondrial defects, underscoring the importance of the enzyme [ ].

Cells containing this mutation were used to test the effect of increased expression of mitochondrial SOD2 on oxidative stress. Targeted lipophilic cation scavenging compound delivery: Reactive oxygen species scavenging compounds are most effective when delivered at the source of the ROS, the IMM [ ]. Molecules to be transported to the mitochondrial interior have to pass the cell membrane and both mitochondrial membranes.

For proper functioning, the molecules must be expressed in an active and stable form. In recent years several vehicles designed to transport therapeutic molecules across mitochondrial membranes have been designed. Targeted mitochondrial delivery can be obtained by i endogenous mitochondrial import, ii facilitated transport across the lipid bilayer, or by iii fusion of closed compartments with the target mitochondria [ ]. Endogenous mitochondrial import strategies have the potential to direct compounds to mitochondria, e.

These peptides enter the mitochondria through the translocases of the inner and outer membrane. The targeting signal has to be cut off after mitochondrial delivery. Several artificial peptide transporters are known to correctly deliver cargo into the mitochondria across the impermeable IMM. The mitochondria penetrating peptide was reported to exhibit efficient cellular uptake and specific mitochondrial localization [ ].

Gramicidin S analogs, peptides based on an antibiotic, can be used to deliver antioxidants and radical scavengers to mitochondria as well [ ].

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