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Mitochondrial Diseases

Mitochondrial diseases are a group of disorders relating to the mitochondria, the organelles that are the "powerhouses" of the eukaryotic cells that comprise higher-order lifeforms (including humans). The mitochondria convert the energy of food molecules into the ATP that powers most cell functions. more...

Mac Ardle disease
Macular degeneration
Mad cow disease
Maghazaji syndrome
Mal de debarquement
Malignant hyperthermia
Mallory-Weiss syndrome
Malouf syndrome
Marburg fever
Marfan syndrome
MASA syndrome
Mast cell disease
MAT deficiency
Maturity onset diabetes...
McArdle disease
McCune-Albright syndrome
Mediterranean fever
Megaloblastic anemia
Meleda Disease
Meniere's disease
Mental retardation
Mercury (element)
Metabolic acidosis
Metabolic disorder
Methylmalonic acidemia
Microscopic polyangiitis
Microtia, meatal atresia...
Miller-Dieker syndrome
Mitochondrial Diseases
Mitral valve prolapse
Mobius syndrome
MODY syndrome
Moebius syndrome
Molluscum contagiosum
MOMO syndrome
Mondini Dysplasia
Mondor's disease
Monoclonal gammopathy of...
Morquio syndrome
Motor neuron disease
Moyamoya disease
MPO deficiency
Mullerian agenesis
Multiple chemical...
Multiple endocrine...
Multiple hereditary...
Multiple myeloma
Multiple organ failure
Multiple sclerosis
Multiple system atrophy
Muscular dystrophy
Myalgic encephalomyelitis
Myasthenia gravis
Mycosis fungoides
Myelodysplastic syndromes
Myeloperoxidase deficiency
Myoadenylate deaminase...
Myositis ossificans

Mitochondrial diseases comprise those disorders that in one way or another affect the function of the mitochondria and/or are due to mitochondrial DNA. Mitochondrial diseases take on unique characteristics both because of the way the diseases are often inherited and because that mitochondria are so critical to cell function. The subclass of these diseases that have neuromuscular disease symptoms are often referred to as a mitochondrial myopathy.

Mitochondrial inheritance

Mitochondrial inheritance behaves differently from the sort of inheritance that we are most familiar with. Regular nuclear DNA has two copies per cell (except for sperm and egg cells). One copy is inherited from the father and the other from the mother. Mitochondria, however, contain their own DNA, and contain typically from five to ten copies, all inherited from the mother (for more detailed inheritance patterns, see mitochondrial genetics). When mitochondria divide, the copies of DNA present are divided randomly between the two new mitochondria, and then those new mitochondria make more copies. As a result, if only a few of the DNA copies inherited from the mother are defective, mitochondrial division may cause most of the defective copies to end up in just one of the new mitochondria. Once more than half of the DNA copies are defective, mitochondrial disease begins to become apparent, this phenomenon is called 'threshold expression'.

It should be noted, however, that not all of the enzymes and other components necessary for proper mitochondrial function are encoded in the mitochondrial DNA. Most mitochondrial function is controlled by nuclear DNA instead.

To make things even more confusing, mutations to mitochondrial DNA occur frequently, due to the lack of the error checking capability that nuclear DNA has. This means that a mitochondrial disorder can occur spontaneously rather than be inherited. Further, sometimes the enzymes that control mitochondrial DNA duplication (and which are encoded for by genes in the nuclear DNA) are defective, causing mitochondrial DNA mutations to occur at a rapid rate.

Defects and symptoms

The effects of mitochondrial disease can be quite varied. Since the distribution of defective DNA may vary from organ to organ within the body, the mutation that in one person may cause liver disease might in another person cause a brain disorder. In addition, the severity of the defect may be great or small. Some minor defects cause only "exercise intolerance", with no serious illness or disability. Other defects can more severely affect the operation of the mitochondria and can cause severe body-wide impacts. As a general rule, mitochondrial diseases are worst when the defective mitochondria are present in the muscles or nerves, because these are the most energy-hungry cells of the body.


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Are Chlorinated Pesticides a Causation in Maternal Mitochondrial DNA Mutations? - mtDNA
From Archives of Environmental Health, 9/1/00 by Jack D. Thrasher

MITOCHONDRIAL DNA (mtDNA) has been mapped completely.[1,2] It encodes 13 mitochondrial subunits, 22 transfer ribonucleic acids (tRNAs), 2 ribosomal RNAs (rRNAs), and polypeptides. Products for mtDNA genome are found in mitochondrial complexes I, III, IV, and V. mtDNA is unique in that it undergoes a high rate of mutation because there is an absence of protective proteins and inadequate DNA repair mechanisms. In addition, mtDNA is inherited maternally; therefore, the only way that the mtDNA sequence can change is by sequential accumulation of mutations along maternal lineages.[3,4] The human oocyte, which contains approximately 200,000 mtDNA (1 per mitochondrion), does not begin replication until the blastocyst stage.[3]

Somatic mutations have been demonstrated in mtDNA from bleomycin,[5] Psoralen,[6] oxidants,[7] aging and degenerative diseases,[8-10] sunlight exposure,[11] cigarette smoking,[12] oxygen and oxidative stress,[13,14] lipid peroxidation,[15] azidothymidine (AZT),[16] antibiotics,[17] and methanol/cyanide exposure.[18] mtDNA mutations are responsible for several mitochondrial syndromes that are inherited maternally.[3,4] However, search of the literature has not revealed a cause for maternal mtDNA mutations. In this editorial, I will describe 5 cases of global developmental delay following exposure of mothers to several organochlorine pesticides (OCPs). I hope the information herein will stimulate other researchers to investigate the effects of exposure to xenobiotics on maternal mtDNA and birth defects.

Five children (3 girls--aged 2 y, 3 y, and 4 y; and 2 boys--aged 2 y and 5 y) were diagnosed with severe global developmental delay and hypotonia. One girl and 1 boy had deficiencies in complexes I and III, and I, respectively. One boy had carnitine deficiency with early myopathy and a suspected mitochondrial defect; currently, he awaits mitochondrial test results. The other 2 girls were severely developmentally delayed, and 1 had an abnormality in [Beta]-hydroxy butyrate and related metabolites. The treating physicians suspected mitochondrial defects.

The 4 mothers lived in the contaminated area as follows: (a) 2 sisters (30 y and 32 y of age, respectively) lived in the contamined area for 10 y (i.e., ages 2 y-12 y and 4 y-14 y, respectively); (b) 1 woman resided in the area from the age of 14 y until age 19 y; and (c) 1 woman who moved to the area at age 6 y or 7 y continues to reside in the area. There is no family history of birth defects in any of the women or their husbands. The husbands were not born or raised in the contaminated area. Furthermore, the earlier-referenced sisters (i.e., item [a]) had 2 half-sisters who were 14 y-16 y older than they, and the half-sisters were not raised in the contaminated area; the 5 children of the half-sisters did not have global developmental delay or hypotonia.

The following OCPs were identified in the contaminated area by the Florida Department of Health: dichlorodiphenyltrichloroethane (DDT), chlordane, toxaphene, aldrin/dieldrin, lindane, endosulfan, and hexachlorobenzene (HCH).[19] The routes of exposure to the residents included contaminated waters in which they played, ingestion of soil, locally consumed fish, locally raised vegetables, and inhalation. No fat biopsies or blood levels measurements were performed for either mothers or children.

Scientific and medical sources reveal the following observations:

1. mtDNA mutations have been observed in human oocytes and embryos. Twenty-three novel mtDNA rearrangements--with deletions, insertions, and duplications--were found and were reportedly unrelated to aging. Significant reductions in the number of oocytes containing mtDNA rearrangements occurred as the oocyte developed from the germinal vesicle to the mature metaphase oocyte.[20,21]

2. Investigators have reported that OCPs occur in human follicular fluid in the ranges of parts per trillion (ppt) and parts per billion (ppb).[22,23] Foster et al.[23] blamed the failure of in vitro fertilization on OCPs in follicular fluid.

3. The ovaries of Rhesus monkeys exposed to HCB resembled human menopausal ovaries. Degenerative changes were observed in the germinal epithelium and ovarian stroma, and a reduction in primary follicles was also noted. Tissues of baby monkeys, which were breast-fed by exposed mothers, contained 2.5-5.5 times more HCB than maternal tissues. In addition, some of the newborns did not survive. HCB also caused toxic effects in primordial germ cells at concentrations that did not cause toxic hepatic effects.[24-27]

4. Cynmolagous monkeys, exposed to 0.01 mg HCB/kg body weight (bw), 0.1 HCB/kg bw, and 10.0 mg HCB/kg bw, had histopathologic and ultrastructural changes in their ovaries. Degenerative changes in thecal and germinal epithelium occurred at all concentrations. Ultrastructural abnormalities were observed in mitochondria of ova and follicular cells. The changes in ovarian structures and ova mitochondria occurred at doses that ranged from ppt to ppb.[28,29]

5. OCPs have been found in human placenta[30] and in human umbilical cord blood in mother/child pairings.[31]

6. OCPs have been isolated from human milk that was reconstituted to concentrations found in the milk and fed to newborn mice. This resulted in reduced white blood cell counts, as well as in toxic effects to liver smooth endoplasmic reticulum and mitochondria. These effects were observed at doses in the ppb to ppm range.[32]

7. OCPs uncouple oxidative phosphorylation, cause oxidative stress, bind to protein complexes and submitochondrial fractions, and alter mitochondrial morphology and function.[33-42]

8. Mutations have been induced in primordial male and female germ cells,[43] oocytes,[44] and zygotes[45-50] of mice. Mice treated with ethylnitrosurea produced male offspring with protein variants associated with microsomal and mitochondrial fractions. These variants were transmitted with either a Mendelian or non-Mendelian inheritable pattern.[51] It should be noted that some zygotic mutations are not typically the result of usual genetic causes.[50]

9. In mouse zygotes, the cytoplasm (mitochondria) mediates both development and oxidation-induced apoptic cell death.[52] Furthermore, several different chlorinated pesticides cause generation of reactive oxygen species, DNA damage, and lactate dehydrogenase leakage. These reactive species may serve as common mediators of apoptosis (programmed cell death).[53]

In conclusion, the observations on these 5 children and their mothers revealed some interesting facts. First, the children had similar symptoms that occur with global developmental delay with hypotonia. Two of the children were diagnosed with mitochondrial defects (complexes I and I, and III), whereas 2 others have suspected mitochondrial defects (i.e., carnitine deficiency and abnormalities of [Beta]-hydroxy butyrate). The 5th child, a 2-y-old female, required additional testing. Second, mothers spent some of their childhoods in the contaminated area. Third, there were no paternal or maternal family histories of developmental defects. Fourth, the 4 fathers neither were raised nor lived near the contaminated site. These facts suggest that the mitochondrial defects and the global developmental delay were environmentally related and were inherited maternally.

Supporting evidence for the above suggestions originates from the scientific and medical literature and includes the following: (a) there is a presence of OCPs in human placenta and umbilical cord blood, as well as in follicular fluid; (b) OCPs produce adverse effects on the ovaries and primordial germ cells of old-world monkeys (old-world monkeys have a menstrual cycle similar to humans); (c) OCPs have an effect on mitochondrial structure and function; (d) OCPs affect neonatal mice; (e) some OCPs are known mutagens; and (f) mtDNA mutations occur in human oocytes and are unrelated to aging. These points are particularly important because mitochondria, under oxidative stress, produce free radicals. Free radicals are suspected mutagens and may cause mtDNA mutations that alter mitochondrial function. The somatic mtDNA mutations listed above are apparently related to the production of free radicals and oxidative stress.

Investigators must conduct further research into the causation of maternal mtDNA mutations--particularly following exposure to mutagenic xenobiotics--and into assessment of the roles of placental transfer of OCPs, as well as determine the effect of breast-feeding on mitochondrion function and human development. We know that it is more efficient to identify inducers of disease and to initiate preventative measures than to seek cures.


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Jack D. Thrasher, Ph.D. Medical/Legal Consultants Environmental Toxicology and Immunotoxicology and Sam-I Trust Alto, New Mexico

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