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About Mitochondrial Medicine

Quick Index Links:
- Mitochondria
- Genetics
- Inheritance
- Mitochondrial Diseases
- Diagnosis
- Treatment
- Schedule an Appointment
- Resources

Mitochondria
Cells are the building blocks of our body, and the proper functioning of each cell contributes to our overall health. Within each cell there are several smaller structures, called organelles, each of which performs a specific task that is necessary for normal cellular function. The nucleus, for example, is an organelle that contains most of the cell’s
DNA, or its genetic blueprint, and is necessary for normal gene expression or read- out of this blueprint. Another organelle, the mitochondrion, can be likened to the power station of the cell, and is necessary to break down sugars, protein, and fats to produce the energy that maintains normal cellular function. An average cell has thousands of mitochondria, although cells that require more energy, such as muscle or brain cells, generally have more. If the mitochondria do not work properly, or if their number is decreased, the cell’s energy supply can be depleted, disrupting normal cellular function, thereby causing disease. A typical cell with its organelles is sown in the figure below.




Mitochondria were originally free-living organisms with their own
DNA and metabolism. As oxygen levels rose in the earth’s atmosphere, these organisms eventually took up residence within the ancestors of our cells, and became dependent upon them for survival.  The host cells benefited from this parasitism, since mitochondria provided them with a more efficient energy production process utilizing molecular oxygen, called oxidative phosphorylation. More than 90% of cellular energy, in the form of adenosine triphosphate (ATP), is currently produced in our cells by the mitochondrial oxidative phosphorylation process. Multicellular organisms could thus not have evolved in their present form without the presence of mitochondria and mitochondrial-mediated energy metabolism. 

As stated above, an average cell contains approximately 4000 mitochondria, although cells that require more energy, such as neurons and/or muscle cells, may have more. Because of the large number of mitochondria in each cell, dysfunction in a few of them has little effect on cellular function. Only when a significant percent of mitochondria malfunction, reaching a critical threshold, do cellular functions become compromised and clinical symptoms occur. Because the ratio of normal to abnormal mitochondria can vary between different cells and/or different body regions, the clinical features of mitochondrial diseases are quite variable and difficult to predict.  Symptoms can thus vary widely, both within various organs in a single individual, and also between individuals.

Mitochondrial diseases were once thought to be rare genetic conditions presenting in childhood. A recent study has shown, however, that mitochondrial DNA mutations may occur in as many as one in 200 individuals. As we learn more about mitochondria and how they function, both within cells and organisms, it has also become clear that mitochondrial dysfunction may be involved in many more common conditions such as diabetes, Parkinson disease, cancer, stroke, and even normal ageing.


Genetics
Genes contain the instructions or blue prints to make proteins that are necessary for cell survival and for cells to carry out their normal functions. Skin cells, for example, make the protein keratin that gives skin its tough yet resilient surface. The genes are located on chromosomes, cellular organelles shaped like small threads that are located within the cell’s nucleus and are composed mainly of DNA. Chromosomes come in pairs, 23 in all, so that each cell contains 46 chromosomes. One chromosome of each pair comes from a person’s mother, while the other comes from their father. Pairs 1 through 22 are called the autosomes and are the same in both men and women. The last pair, however, contains the sex chromosomes. Men have both an X and a Y sex chromosome: an X from their mother, and a Y from their father. In contrast, women have two X chromosomes. The human genome consists of the DNA in set of 23 chromosomes and encodes approximately 20-25, 000 genes.




Each mitochondrion also has its own chromosome separate from the 23 pairs of chromosomes located within the nucleus of the cell. The mitochondrial chromosome is a small circular
DNA that encodes 37 genes not contained within the nuclear genome. Proteins that are made from these genes are located within the mitochondrion, and are necessary for the mitochondrion to function properly. Since the mitochondrion requires several hundred different proteins for its normal function, however, additional mitochondrial proteins are also encoded by the nuclear genome. Mitochondria thus have proteins produced from both the nuclear and the mitochondrial chromosomes. Genetic disorders that alter mitochondrial function can be caused by mutation in one of the 23 pairs of chromosomes located within the nucleus of the cell, or by mutation in the chromosome located within each mitochondrion.

Each mitochondrion contains more than 10 copies of the mitochondrial genome, so that an average cell has thousands of copies of mtDNA. For this reason, mutant and wild type mtDNAs can co-exist within the same mitochondrion and/or the same cell. If all the mtDNAs are identical, this is called homoplasmy; if some of the mtDNA have a different sequence, however, this is called heteroplasmy. The existence of mixed populations of mtDNAs provides the basis for some of the heterogeneity of mitochondrial disease, since a single mitochondrion can express both normal and mutant mitochondrial proteins. In addition, the presence of heteroplasmy also accounts for the heterogeneity of genetic transmission of these diseases as well as differences in clinical symptoms between individuals.


Inheritance

Mitochondrial disorders can be inherited from one or both parents due to genetic changes in either the nuclear or mitochondrial genomes. The family tree, or pedigree, of a person suspected of having one of these diseases may help both to determine the inheritance pattern for the disease, and to determine its diagnosis. If several family members are suspected of having a mitochondrial disorder, knowing the inheritance pattern of the disease may also predict who within the family might be at risk for having this condition.  The main types of inheritance patterns for mitochondrial diseases are shown below. The X-linked, autosomal dominant and autosomal recessive patterns are a result of mutations of genes contained within the nuclear genome; the maternal or mitochondrial inheritance pattern is a result of mutations within the mitochondrial genome.




Illustration from Genetic Counseling Aids, 4th edition, Copyright 2002, permission of use granted by Greenwood Genetic Center.


Illustration from Genetic Counseling Aids, 4th edition, Copyright 2002, permission of use granted by Greenwood Genetic Center.


Illustration from Genetic Counseling Aids, 4th edition, Copyright 2002, permission of use granted by Greenwood Genetic Center.



Illustration from Genetic Counseling Aids, 4th edition, Copyright 2002, permission of use granted by Greenwood Genetic Center.



Mitochondrial Diseases
Mitochondrial diseases, caused by mutation in either a nuclear or mitochondrial gene, usually affect many different parts of the body. In addition, not every person with the same mitochondrial disease has the same symptoms, which may also change over time. For these reasons, mitochondrial diseases are often difficult to diagnose. Some of the more common symptoms of a mitochondrial disease are listed below.

  • Loss of motor control (inability to voluntarily move muscles)

  • Muscle weakness and pain

  • Gastro-intestinal (digestive) disorders

  • Swallowing difficulties

  • Poor growth

  • Cardiac (heart) disease

  • Liver disease

  • Diabetes

  • Respiratory (breathing) complications

  • Seizures

  • Visual and/or hearing problems

  • Lactic acidosis (lack of oxygen to the cells that can lead to rapid breathing, vomiting and stomach pain)

  • Developmental delays

  • Susceptibility to infection

      The function of mitochondria, however, can also be affected in common conditions, such as diabetes, Parkinson disease, multiple sclerosis, stroke and heart disease. Mitochondrial dysfunction has even been implicated in causing normal aging. Research to identify new treatments to improve mitochondrial function will thus not only be helpful for patients with traditional mitochondrial diseases, but also for the treatment of individuals with these more common conditions.

       
      Diagnosis
      Since there is a wide range of clinical symptoms caused by mitochondrial dysfunction, no one of which is specific for any known mitochondrial disease, the diagnosis of a mitochondrial disease can be a challenge.  Genetic testing can sometimes identify a change in a person’s DNA that can be used to confirm the diagnosis of a mitochondrial disease. In many (or most) cases, however, a mitochondrial disorder may be suspected, but cannot be definitely confirmed by testing.

      Some tests that may be done to determine the likelihood of a mitochondrial condition include:

      • Blood tests
      • Urine tests
      • Muscle biopsy (a small piece of the muscle is removed and examined under a microscope)
      • Brain MRI (pictures of the brain)
      • EEG (test to evaluate for seizures)
      • EKG and echocardiogram (tests to check for heart problems)
      • Audiology evaluation (for problems with hearing)
      • Ophthalmology examination (to evaluate vision)
      • Obtaining a pedigree (collecting the patient’s medical and family history)
      • Genetic testing  (on a blood sample and/or muscle biopsy)

      Testing is usually individualized for each patient, and is often focused on the specific set of symptoms and body regions involved. Once testing is complete, however, a specific diagnosis of a mitochondrial disease may still not be possible.  

                 

      Treatment
      There are no well-accepted treatments for mitochondrial diseases. Some physicians, however, do prescribe specific vitamins to patients. For all patients, optimizing their overall health is very important.

       
      Scheduling an Appointment
      Our Mitochondrial Clinic is held in conjunction with the Muscular Dystrophy Association (MDA) clinics at the Detroit Medical Center. Please contact us by phone at (313) 577-1698 or by email at mitoclinic@med.wayne.edu for more information or to schedule an appointment.

      Any medical records you have that might be related to a mitochondrial condition should be brought to your appointment.  Please arrive approximately 15 minutes prior to your appointment to complete appropriate paperwork.  Besides a physician, you may also be meeting with a genetic counselor, a physical therapist, a MDA HCSC (Health Care Service Coordinator), and possibly students or other trainees. As this clinic is a multidisciplinary clinic with many individuals, please plan to spend several hours at the clinic. 

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