Posts Tagged ‘Leigh syndrome’

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


Leigh syndrome is one of the hundreds of so-called mitochondrial diseases, which are caused by defects in the mitochondria that produce 90 percent of the body’s energy. These disorders are rare; about 1,000 to 4,000 babies in the United States are born with one every year. But they are devastating and can result in grave impairment of nearly any bodily system. They are largely untreatable, uniformly incurable and very difficult to screen.


Leigh syndrome is a terrible disease. It emerges shortly after birth and claims one major organ after another. Movement becomes difficult, and then impossible. A tracheotomy and feeding tube are often necessary by toddlerhood, and as the disease progresses, lungs frequently have to be suctioned manually. Most children with the condition die by the age of 5 or 6.


Scientists have devised a procedure called mitochondrial replacement therapy (M.R.T.) that involves transplanting the nucleus of an affected egg (mitochondrial diseases are passed down from the mother’s side) into an unaffected one whose nucleus has been removed. The procedure is sometimes called “three-parent in vitro fertilization”. Mitochondria contain a minuscule amount of DNA, any resulting embryo would have mitochondrial DNA from the donor egg and nuclear DNA from each of its parents.


After decades of careful study in cell and animal research M.R.T. is now finally being tested in human clinical trials by doctors in Britain (no births confirmed yet officially). In the United States, however, this procedure is effectively illegal. M.R.T. does not involve altering any genetic code. Defective mitochondria are swapped out for healthy ones.


Mitochondrial DNA governs only a handful of basic cellular functions. It is separate from nuclear DNA, which helps determine individual traits like physical appearance, intelligence and personality. That means M.R.T. cannot be used to produce the genetically enhanced “designer babies” and thus should be allowed in humans. But, there is no way to know how safe or effective M.R.T. is until doctors and scientists test it in humans.








Read Full Post »

Author and Curator: Ritu Saxena, Ph.D.

Consultants: Aviva Lev-Ari, PhD, RN and Pnina G. Abir-Am, PhD


Section I   : Mitochondrial diseases and molecular understanding

Section II  : Diagnosis and therapy of mitochondrial diseases

Section III: Mitochondria, metabolic syndrome and research


Mitochondrial cytopathy in adults – current understanding:

Mitochondrial cytopathies are a diverse group of inherited and acquired disorders that result in inadequate energy production leading to illnesses. Several syndromes have been linked to mutations in mitochondrial DNA. Some key features common to mitochondrial diseases are listed as follows:

  • Diverse manifestations of mitochondrial diseases: Although all mitochondrial diseases have the same characteristic of inadequate energy production as compared to the demand, they seem to show diverse manifestations in the form of organs being affected, age of onset and the rate of progression. Reason lies in the unique genetic makeup of mitochondria. The percentage of mtDNA carrying defects varies when the ovum divides and one daughter cells receiving more defective mtDNA and the other receiving less. Hence, successive divisions may lead to accumulation of defects in one of the developing organs or tissues. Since the process in which defective mtDNA becomes concentrated in an organ is random, this may account for the differing manifestations among patients with the same genetic defect. Also, somatic mutations and mutations occurring as a result of exposure to environmental toxins may cause mitochondrial diseases.

As stated by Robert K. Naviaux, founder and co-director of the Mitochondrial and Metabolic Disease Center (MMDC) at the University of California, San Diego;  

“It is a hallmark of mitochondrial diseases that identical mtDNA mutations may not produce identical diseases…the converse is also true, different mutations can lead to the same diseases.”

  • Postmitotic tissues are more vulnerable to mitochondrial diseases: Postmitotic tissues such as those in the brain, muscles, nerves, retinas, and kidneys, are vulnerable for several reasons. Apart from the fact that these tissues have high-energy demands, healthier neighboring cells unlike that observed in skin cannot replace the diseased cells. Thus, mutations in mtDNA accumulate over a period of time resulting in progressive dysfunction of individual cells and hence the organ itself.
  • High rate of mtDNA mutation: MtDNA mutates at rate that is six-seven times higher than the rate of mutation of nuclear DNA. First reason is the absence of histones on mtDNA and second is the exposure of mtDNA to free radicals due to their close proximity to electron transport chain. Additionally, lack of DNA repair enzymes results in mutant tRNA, rRNA and protein transcripts

Spectrum of mitochondrial diseases:

Following is the list of mitochondrial diseases occurring as a result of either mtDNA mutations, alteration in mitochondrial function or those diseases that sometimes might be associated with mitochondrial dysfunction.

  • Disorders associated with mtDNA mutations-

MELAS, MERRF, NARP, Myoneurogastrointestinal disorder and encephalopathy (MNGIE), Pearson Marrow syndrome Kearns-Sayre-CPEO, Leber hereditary optic neuropathy (LHON), Aminoglycoside-associated deafness, Diabetes with deafness

  • Mendelian disorders of mitochondrial function related to fuel homeostasis-

Luft disease, Leigh syndrome (Complex I, COX, PDH), Alpers Disease, MCAD, SCAD, SCHAD, VLCAD, LCHAD, Glutaric aciduria II, Lethal infantile cardiomyopathy, Friedreich ataxia, Maturity onset diabetes of young Malignant hyperthermia, Disorders of ketone utilization, mtDNA depletion syndrome, Reversible COX deficiency of infancy, Various defects of the Krebs Cycle, Pyruvate dehydrogenase deficiency, Pyruvate carboxylase deficiency, Fumarase deficiency, Carnitine palmitoyl transferase deficiency

  • Disorders sometimes associated with mitochondrial function-

Hemochromatosis, Wilson disease, Batten disease, Huntington disease, Menkes disease, Lesch-Nyhan syndrome, Aging, Type II diabetes mellitus, Atherosclerotic heart disease, Parkinson disease, Alzheimer dementia, Congestive heart failure, Niacin-responsive hypercholesterolemia, Postpartum cardiomyopathy, Alcoholic myopathy, Cancer metastasis, Irritable bowel syndrome Gastroparesis-GI dysmotility, Multiple sclerosis, Systemic lupus erythematosis, Rheumatoid arthritis.



Owing to the diversity of symptoms, there is no accepted criterion for diagnosis. Also, due to overlapping symptoms of several diseases with those of mitochondrial dysfunction illnesses, it is important to evaluate the patient for other conditions. A diagnosis could involve combination of molecular genetic, pathologic, or biochemical data in a patient who has clinical features consistent with the diagnosis including mutational analysis on blood lymphocytes and possibly muscle biopsy for visual and biochemical analysis.

The two main biochemical features in most mtDNA disorders are:

  1. Respiratory chain deficiency and
  2. Lactic acidosis.

Skeletal muscle is chosen to study the pathogenic consequence of mtDNA mutations because of the formation of ragged-red fibers (RRF) through mitochondrial proliferation and massive mitochondrial accumulation in many pathogenic situations. RRF can be detected in two ways. Mitochondrial fibers in a subset of these fibers are shown by red or purple stained area by Gomori trichrome stain; the normal or less-affected fibers stain blue or turquoise. Deep purple areas show accumulations of mitochondria as activity of succinate dehydrogenase (SDH) in the case of mitochondrial mutation.

The primary care physician should remember this relatively simple rule of thumb: “When a common disease has features that set it apart from the pack, or involves 3 or more organ systems, think mitochondria.”


There are no cures for mitochondrial diseases; therefore, the treatment is focused on alleviating symptoms and enabling normal functioning of the affected organs. Most patients have used cofactor and vitamins; however, there is no overwhelming evidence that they are helpful in most patients.

  • Coenzyme Q10 (CoQ10) is the best-known cofactor used in treating mitochondrial cytopathies with no known side effects. CoQ10, residing in the inner mitochondrial membrane, functions as the mobile electron carrier and is a powerful antioxidant with benefits such as reduction in lactic acid levels, improved muscle strength, decreased muscle fatigue and so on.
  • Levocarnitine (L-carnitine, carnitine), is a cofactor required for the metabolism of fatty acids. Levocarnitine therapy improves strength, reversal of cardiomyopathy, and improved gastrointestinal motility, which can be a major benefit to those with poor motility due to their disease. Intestinal cramping and pain are the major side effects.
  • Creatine phosphate, synthesized from creatine can accumulate in small amounts in the body, and can act as storage for a high-energy phosphate bond. Muscular creatine may be depleted in mitochondrial cytopathy, and supplemental creatine phosphate has been shown to be helpful in some patients with weakness due to their disease.
  • B Vitamin, are necessary for the function of several enzymes associated with energy production. The need for supplemental B vitamin therapy is not proven, aside from rare cases of thiamine (vitamin B1)-responsive pyruvate dehydrogenase deficiency.

Research – Restriction enzyme for gene therapy of Mitochondria diseases:

Mitochondrial DNA (mtDNA) is the only extrachromosomal DNA in humans and defects in this genome are now recognized as important causes of various diseases. Presently, there is no effective treatment for patients suffering from diseases that harbor mutations in mtDNA.

Tanaka et al discovered a gene therapy method to treat a mitochondrial disease associated with mtDNA heteroplasmy. Heteroplasmy is where mutant and wild-type mtDNA molecules co-exist within cells. This syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) is caused by mutations in mtDNA leading to amino acid replacement in the resulting protein that codes for a subunit of mitochondrial ATP synthase. Level of mutant mtDNA is crucial for the disease as above a certain threshold level of mtDNA, the disease becomes biochemically and clinically apparent. Authors hypothesized that a possible method to treat patients was by selectively destroying mutant mtDNA, thereby only allowing propagation of wild-type mtDNA. Since restriction endonucleases can recognize highly specific sequences, they were utilized for gene therapy. Tanaka et al utilized Sma1, a restriction endonuclease to destroy mutant mtDNA, leading to increase in wild-type mtDNA levels.

Thus, authors concluded, “ the present results indicate that the use of a mitochondrion-targeted restriction enzyme which specifically recognizes a mutant mtDNA provides a novel strategy for gene therapy of mitochondrial diseases.”



Mitochondria are double-membrane organelles located in the cytoplasm and often referred to as the “powerhouse” of the cell. In simple terms, they convert energy into forms that are usable by the cell. Mitochondria are semi-autonomous in that they are only partially dependent on the cell to replicate and grow. They have their own DNA, ribosomes, and can make their own proteins. They are the sites of cellular respiration that generates fuel for the cell’s activities. Mitochondria are also involved in other cell processes such as cell division, cellular growth and cell death. Multiple essential cellular functions are mediated by thousands of mitochondrial-specific proteins, encoded by both the nuclear and mitochondrial genomes.

Interestingly, mitochondria take on many different shapes and along with serving several different metabolic functions. In fact, each mitochondrion’s shape is characteristic of the specialized cell in which it resides. The number of mitochondria too varies in difference cell types, with as high as 500-2000 in some nucleated cells and as low as zero in RBCs and 2-6 in platelets.

The standard sequence to which all human mtNDNA is compared is referred to as the “Cambridge Sequence.” It was sequenced from several different human mtDNAs by a Medical Research Council (MRC) labora- tory based at Cambridge, UK, in 1981 and as a part of this work, Fred Sanger, the received his second Nobel Prize. Several variations in the form of polymorphisms are observed from the Cambridge sequence in the mtDNA of different individuals.

Metabolic syndrome:

Metabolic syndrome is a cluster of conditions — increased blood pressure, a high blood sugar level, excess body fat around the waist or abnormal cholesterol levels — that occur together, increasing your risk of heart disease, stroke and diabetes. Metabolic syndrome is becoming more and more common in the United States. In the future, it may overtake smoking as the leading risk factor for heart disease. In general, a person who has metabolic syndrome is twice as likely to develop heart disease and five times as likely to develop diabetes as someone who doesn’t have metabolic syndrome.

The five conditions described below are metabolic risk factors. You must have at least three metabolic risk factors to be diagnosed with metabolic syndrome.

  • A large waistline. This also is called abdominal obesity or “having an apple shape.” Excess fat in the stomach area is a greater risk factor for heart disease than excess fat in other parts of the body, such as on the hips.
  • A high triglyceride level (or you’re on medicine to treat high triglycerides). Triglycerides are a type of fat found in the blood.
  • A low HDL cholesterol level (or you’re on medicine to treat low HDL cholesterol). HDL sometimes is called “good” cholesterol. This is because it helps remove cholesterol from your arteries. A low HDL cholesterol level raises your risk for heart disease.
  • High blood pressure (or you’re on medicine to treat high blood pressure). Blood pressure is the force of blood pushing against the walls of your arteries as your heart pumps blood. If this pressure rises and stays high over time, it can damage your heart and lead to plaque buildup.
  • High fasting blood sugar (or you’re on medicine to treat high blood sugar). Mildly high blood sugar may be an early sign of diabetes.

Role of Mitochondria in Metabolic Syndrome & Diabetes:

Impaired mitochondrial function has recently emerged as a potential causes of insulin resistance and/or diabetes progression, risk factors of metabolic syndrome.

Mitochondria plays several key functions including generation of ATP, and generating metabolites via Tricarboxylic acid cycle that function in cytosolic pathways, oxidative catabolism of amino acids, ketogenesis, urea cycle; the generation of reactive oxygen species (ROS); the control of cytoplasmic calcium; and the synthesis of all cellular Fe/S clusters, protein cofactors essential for cellular functions such as protein translation and DNA repair. These roles define the mitochondria to be involved in metabolic homeostasis and hence, a major candidate for metabolic syndrome and its associated risk factor including diabetes, obesity and insulin resistance.

Research and Therapeutic relevance:

Understanding the underlying molecular mechanism of aberrant role of mitochondria is important in developing therapeutic agents for mitochondria-associated diseases. In the recent issue of Mitonews, several papers have been published using the products of MitoSciences, which describe research pertaining to the importance of mitochondria in obesity and diabetes. Some recent research articles based on mitochondrial research (also mentioned in MitoNews) have been briefly discussed here:

  • Metabolic inflexibility and Metabolic syndrome: Metabolic inflexibility is defined as the failure of insulin-resistant patients to appropriately adjust mitochondrial fuel selection in response to nutritional cues. Although the phenomenon has been emphasized an important aspect of metabolic syndrome, the molecular mechanisms have not yet been fully deciphered. In a recent article by Muoio et al, published in Cell Metabolism journal, essential role of the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT) has been identified in regulating substrate switching and glucose tolerance. CrAT regulates mitochondrial and intracellular Carbon trafficking by converting acetyl-CoA to its membrane permeant acetylcarnitine ester. Using muscle muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation, authors have suggested a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility.
  • Rosiglitazone and obesity: Eepicardial adipose tissue (EAT) has been described in humans as a functioning brown adipose tissue (BAT) and has been shown in animal models to have a lower glucose oxidation rate and higher fatty acid (FA) metabolism. In obese individuals, epicardial adipose tissue (EAT) is “hypertrophied”. EAT is a source of BAT may be a source of proinflamatory cytokines. Distel et al published their studies using a rat model of obesity and insulin resistance treated with rosiglitazone. They observed that rosiglitazone, promoted a BAT phenotype in the EAT depot characterized by an increase in the expression levels of genes encoding proteins involved in mitochondrial processing and density PPARγ coactivator 1 alpha (PGC-1α), NADH dehydrogenase 1 and cytochrome oxidase (COX4) resulting in significant up-regulation of PGC1-α and COX4 protein. The authors concluded that PPAR-γ agonist could induce a rapid browning of the EAT that probably contributes to the increase in lipid turnover. Thus, important insights into the mechanism of fat metabolism and involvement of mitochondrial proteins with a therapy were presented in the article.
  • Mitochondrial dysfunction and diabetic neuropathy: Animal models of diabetic neuropathy show that mitochondrial dysfunction occurs in sensory neurons that may contribute to distal axonopathy. The adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signalling axis senses the metabolic demands of cells and regulates mitochondrial function. Studies in muscle, liver and cardiac tissues have shown that the activity of AMPK and PGC-1α is decreased under hyperglycaemia. Chowdhury et al using type 1 and type 2 diabetic rat and mice models studied the hypothesis that deficits in AMPK/PGC-1 signalling in sensory neurons underlie impaired axonal plasticity, suboptimal mitochondrial function and development of neuropathy. The authors have shown there is a significant reduction in phospho-AMPK, phopho-ACC, total PGC-1α, NDUFS3and COXIV in sensory neurons of the dorsal root ganglia of 14 week old diabetic mice with marked signs of thermal hypoalgesia. These results were associated with an impaired neuronal bioenergetic profile and a decrease in the activity of mitochondrial complex I, complex IV and citrate synthase. The fact that resveratrol treatment reversed the changes observed in vitro and in vivo suggest that the development of distal axonopathy in diabetic neuropathy is linked to nutrient excess and mitochondrial dysfunction via defective signalling of the AMPK/PGC-1α pathway.
  • ROS and diabetes: Mitochondria generated reactive oxygen species (ROS) has been associated with kidney damage occurring in diabetes. Rosca et al, published an article investigating the source and site of ROS production by kidney cortical tubule mitochondria in streptozotocin-induced type 1 diabetes in rats. The authors observed that in diabetic mitochondria, the fatty acid oxidation enzymes were elevated with increased oxidative phosphorylation and increased ROS production. The authors observed ROS production with fatty acid oxidation remained unchanged by limiting electron flow in ETC complexes, changes in ETC substrate processing and that the ROS supported by pyruvate also remained unaltered. The authors hence concluded that mitochondrial fatty acid oxidation is the source of increased ROS production in kidney cortical tubules in early diabetes


Read Full Post »