The MMDC operates at the interface of basic science and clinical medicine. The diagnosis, treatment and prevention of mitochondrial disease requires both basic and clinical research. Today, treatment of these diseases is very difficult and despite our best efforts, continued deterioration is often the outcome. We believe that the reason for the lack of really effective therapy is because there is much that we do not yet understand about how mitochondria work. Basic research is crucial to winning the battle against mitochondrial disease and this research must go hand in hand with clinical research into currently available treatments. Our mission is to help tomorrow's children as well as those who are afflicted today.

Basic Research

1. The mechanisms of mitochondrial DNA replication

Many mitochondrial diseases are known to be due to abnormalities of mitochondrial DNA. Understanding the fundamental mechanisms of mitochondrial DNA replication is the focus of a major MMDC effort. Pioneering work at the MMDC has identified a previously unsuspected viral-like mechanism of mitochondrial DNA replication- Reverse Transcription.

2. DNA Polymerase deficiency in mitochondrial disease

A complex protein, DNA Polymerase , is essential for replication of mitochondrial DNA and growth of normal mitochondria. Using an assay developed at the MMDC we are searching for abnormalities of polymerase function and have identified a number children with deficiency of DNA Polymerase . One of these children appears to have suffered from a complete deficiency of DNA Polymerase . We are currently characterizing the mechanisms and effects of DNA Polymerase deficiency which may be a common cause of the recently described mitochondrial DNA depletion syndrome.

3. Canine mitochondrial myopathy

Animal models of mitochondrial disease are desparately needed to further our basic understanding and to help in the development of effective treatments. Working with the UCSD Comparative Neuromuscular Laboratory we have the opportunity to study muscle samples from dogs and other animals from around the US. These samples are sent from sick animals to help veterinarians in their treatment and diagnosis. We have found many dogs with mitochondrial disease and we are actively researching the causes with the hope of identifying a suitable animal model to help both the dogs and our human patients.

4. Gene therapy of mitochondrial disease

MMDC basic research is paving the way to the possibility of gene therapy for mitochondrial disease. Our research into mitochondrial replication has provided a number of novel ideas which we plan to pursue.

Basic/ Clinical Research

5. Electron transport defects in Parkinson's disease

We have published evidence that patients with early Parkinson's disease have lower activities of important mitochondrial energy producing systems when compared to matched controls and spouses. These changes occur early in the disease, cannot be attributed to treatment and may be causative. We have miniaturized our mitochondrial isolation techniques and can now work with small blood samples allowing an expansion of these studies and correlation with other important factors such as levels of the anti-oxidant coenzyme Q₁₀.

6. Screening the mitochondrial genome in Parkinson's disease and movement disorders

The underlying cause of the mitochondrial abnormalities in Parkinson's disease may lie in the mitochondrial DNA. Pioneering the use of a method of screening DNA known as DGGE in mitochondria we are searching for abnormalities in children with movement disorders and adults with Parkinson's disease.

7. Miniaturization of mitochondrial diagnostic testing

Working with children it is particularly important to be able to gain as much information from as small a sample as possible. Research in the MMDC has focused on the development of methods for performing diagnostic tests on tiny samples. We routinely extract and study mitochondria from as little as 15 mls of blood or 300 mg. of muscle tissue. Research into further miniaturizing mitochondrial testing is underway.

8. Diagnostic analysis of mitochondrial DNA

Identification of new causes of mitochondrial DNA disease is dependent on the development of better methods of diagnosis. In particular screening methods are needed to allow a more comprehensive look at the 16569 nucleotide bases comprising the mitochondrial genome. Work in the MMDC resulted in the development of novel new diagnostic techniques for the identification of mitochondrial DNA disease from blood and muscle.

9. Mechanisms of deterioration in mitochondrial disease

A common feature of mitochondrial disease is the tendency of the patient to deteriorate at the time of intercurrent illness - usually a viral infection. Treatment to prevent such deteriorations is dependent on an understanding of why this happens. Research in the MMDC is directed towards answering this important question.

Clinical and Therapeutic Research

10. Clinical research into the causes and effects of mitochondrial disease

Our work at the MMDC attracts patients with mitochondrial disease from around the US and abroad. Adults and children are studied in detail in the NIH funded General Clinical Research Center at UCSD. Mitochondria are in every organ and a hallmark of the mitochondrial diseases is their multisystem nature. Studies are directed towards understanding the effects of the mitochondrial disease in the individual patient with the goal of achieving a molecular diagnosis and identifying the best treatment for each patient. Through the study of many patients the MMDC is expanding the knowledge base about the effects of mitochondrial disease and the appearance or phenotype of common and uncommon mitochondrial problems.

11. Dietary and cofactor treatment of mitochondrial disease

In hospital study of mitochondrial disease patients allows the study of the effects of therapeutic diet manipulation. We hope to develop guidelines for other physicians working with mitochondrial diseases about the most effective diet and cofactor treatments.

12. Coenzyme Q treatment in Parkinson's disease

Pilot studies at the MMDC were encouraging and have lead to submission of a proposal for a multicenter trial to assess the effect of coenzyme Q₁₀ in Parkinson's disease.

13. Dichloroacetate treatment of lactic acidosis in mitochondrial disease

One of the effects of mitochondrial failure is the accumulation of lactic acid in the body. When large quantities are accumulated lactate can be damaging. An unblinded experimental treatment protocol of dichloroacetate treatment has been underway for 2 years. Results are encouraging but it has become apparent that a larger study will be needed to answer the questions which have arisen about efficacy and risks of this treatment. We hope to be able to identify which patients will benefit from dichloroacetate treatment and which patients will not.

14. Neuroimaging in Leigh's Syndrome

Leigh's syndrome is a devastating childhood form of mitochondrial disease. Diagnosis is often difficult and neuroimaging studies are often used to help. In our study of over 20 patients with Leigh's syndrome we have found previously unreported patterns of disease on magnetic resonance brain images and in some patients dramatic changes over time. This research will improve the clinical diagnosis of Leigh's syndrome.

Acknowledgments: Research at the MMDC is supported by research funding from the following sources