What are Mitochondria?

Mitochondria are small complex structures, which exist in every cell of the body (except red blood cells).
The mitochondrion has been called the ‘powerhouse’ of the cell, as these tiny structures produce most of
the energy, which we all need to grow and live. Those organs in the body, which require a lot of energy
to work properly, are particularly dependent on well functioning mitochondria. The most energy dependent
organs are the brain, heart, skeletal muscle, kidney, endocrine glands and bone marrow and these are the
organ systems commonly affected in mitochondrial diseases.

There are from one to several hundred mitochondria in each cell and each mitochondrion contains the
complex molecules necessary to carry our energy making chemical reactions. Mitochondria perform many
functions necessary for cell metabolism but the energy producing pathways are the most important. These
pathways allow us to break down carbohydrate, fat and oxygen to live. Electrons from these food molecules
are passed down a series of complex molecules called the electron transport chain. The final molecule in the
chain, cytochrome oxidase, passes the electrons to oxygen

One unique feature of mitochondria is that they have there own DNA molecules, mitochondrial DNA, which
carries the genes containing the genetic message for several critical components of the electron transport chain.
 

What is a Mitochondrial Disease?

When enough mitochondria are not working correctly a disease may result. Mitochondrial diseases often involve
the brain because of the tremendous energy requirements of the brain cells. Mitochondrial diseases are very
variable in their features so called clinical heterogeneity.

The variability results from the fact that different organ systems contain different amounts of diseased mitochondria
and only those tissues with a high percentage of diseased mitochondria will be functional impaired. Mitochondrial
diseases are whole body diseases but the exact features of the disease vary from one patient to another. Some
patients will have predominately brain disease or nerve disease. Others will have muscle disease (mitochondrial
myopathy), cardiac disease (cardiomyopathies), endocrine, renal or bone marrow disease or a mixture of these
and or other features.

Many mitochondrial diseases result in the accumulation of organic acids in the body. These are usually normal
metabolic intermediates but when present in excess, the acidosis itself may be damaging or even life-threatening.
Lactic acid accumulation is a common problem in mitochondrial diseases.

We used to think of mitochondrial diseases as rare childhood disorders. Recently it has been discovered that many
commoner disorders such as diabetes and ischemic heart disease have, in some cases, a mitochondrial basis. Also,
diseases of aging such as Parkinson’s disease and Alzheimer’s disease may result in part from mitochondrial
failure (The role that mitochondrial abnormalities play in the cause of these diseases remains to be established).
In fact, the aging process itself may be due to a lifetime of damage to mitochondria through oxidative stress and
accumulated damage to mitochondrial proteins and mitochondrial DNA.
 

Genetics of Mitochondrial Diseases?

Some mitochondrial diseases are clearly inherited and those involving mitochondrial DNA may be inherited
through the maternal side of the family as almost all mitochondria come from the mother. Most inherited
mitochondrial diseases however are so called nuclear DNA defects with inheritance from either the mother or
father, or in most cases both. This latter inheritance pattern is termed autosomal recessive and in this case the
risk of reoccurrence in a sibling is 25% or one in 1 in 4. Most childhood onset mitochondrial diseases are inherited
although in some cases the affected child seems to be the only affected family member.

Diseases resulting from mitochondrial deletions of large parts of the mitochondrial DNA molecule are usually
sporadic without other affected family members. Genetic counselling is complex for mitochondrial diseases.

Pre-natal testing is only available for a few disorders.
 

How are Mitochondrial Diseases diagnosed?

Because of the multiple organ systems involved and the variation in the age of onset, mitochondrial diseases
may be difficult to recognize. Even within the same family the same disease may affect individuals differently.
A severe childhood disease such as Leigh’s syndrome may occur in the same family with later onset adult
neurodegenerative disease. In some families mitochondrial myopathy has found some members with deafness
and diabetes in others strokes along with a mixture of other symptoms. As well as the history and physical
examination, blood and urine specialized tests together with brain CT or MRI scanning and skin and muscle
biopsy are often needed to make a diagnosis. Patients should be referred as soon as possible to a specialist
centre with expertise in metabolic and mitochondrial diseases.

What Treatments are available? (1)

In the New Millennium treatments for mitochondrial diseases are not very effective. Some effects of these
diseases can be treated such as cardiac arrhythmia, seizure disorders, renal bicarbonate loss and hypoglycaemia.

When lactic acid accumulation seems to be a major problem an experimental drug Dichloroacete DCA, will lower
the lactic acid. Although conclusive evidence of efficacy is not yet available, most doctors working with
mitochondrial diseases treat their patients with cofactors and vitamins, which are thought to help impaired
metabolic pathways. These treatments include combinations of Coenzyme Q10, L-Carnitine, Niacin, Thiamine,
Biotin and Riboflavin. Special diets can be helpful.

Some patient’s benefit by high fat diets with restriction of simple carbohydrates. Fructose restriction may help.

Other patients need high carbohydrate intake with particular supplementation of complex carbohydrates such as
uncooked cornstarch.

Only with a through medical evaluation, best carried out in a centre specializing in metabolic & mitochondrial
diseases, can the optimal treatment regime for each patient be chosen.
 

What does the future hold? (1a)

There is no convincing evidence to date of any clear benefit of drug therapies in most archetypal mitochondrial
disorders or those neurodegenerative conditions with evidence of mitochondrial dysfunction, and therefore
attention has turned to the development of genetic therapies and the possibility of Neuro protection.

New horizons and hopes may lie with genetic strategies. Techniques for manipulating the mitochondrial genome
are now being investigated. Whereas nuclear manipulation would necessitate treatment for life, manipulation of the mitochondrial genome would result in a one-off treatment thus providing a “CURE” for Mitochondrial Disorders.
 

Links to sites about Mitochondrial Disease:
 United Mitochondrial Disease Foundation    -  The United Mitochondrial Disease Foundation is redefining hope
                                                                  for families affected by mitochondrial diseases -- hereditary disorders,
                                                                  now considered as common as childhood cancers, that affect the
                                                                  cell's ability to produce life-sustaining energy.
 MDA / Quest 6-4 / Mitochondrial Myopathy  - This is a two-part Quest series about mitochondrial myopathy.
                                                                  This article covers the basic biology of mitochondria and explains
                                                                   inheritance patterns and determinants of severity in mitochondrial
                                                                   diseases. Part 2 will discuss diagnosis and treatment, including a
                                                                   look at new information about mitochondrial diseases in the research
                                                                   pipeline.