A Mitochondrial Basis for Metabolic Syndrome
Team Leader:
- Douglas C. Wallace, Ph.D., University of California, Irvine, Colleges of Medicine and Biological Sciences
Key Investigators:
- J. Jay Gargus, M.D., Ph.D.,
University of California, Irvine - F. Sherwood Rowland, Ph.D.,
University of California, Irvine
- Donald R. Blake, Ph.D.,
University of California, Irvine - Bruce J. Tromberg, Ph.D., Beckman Laser Institute, University of California, Irvine
Team Disciplines:
Biological Chemistry, Ecology & Evolutional Biology, Physiology & Biophysics, Chemistry, Biomedical Engineering
Abstract
The “Metabolic Syndrome” encompasses diabetes and hyperglycemia, obesity and hypertrigiyceridemia, and hypertension. Considerable biochemical and genetic evidence has now accumulated implicating mitochondrial defects in the etiology of these symptoms. We now propose a series of biochemical, physiological and genetic studies to test this mitochondrial hypothesis for the Metabolic Syndrome and to develop more effective diagnostic tools for this class of diseases.
The Metabolic Syndrome patients to be studied include individuals of Chinese descent living in the southwestern United States (US) seen at the University of California, Irvine (UCI) Health Science Center and in Taipei, Taiwan seen at the National Taiwan University Hospital. Metabolic Syndrome patients and matched controls for the southwestern US will be subjected to detailed physiological and biochemical analysis. First, these subjects’ mitochondrial function will be evaluated using our advanced diagnostic procedures including pulmonary exercise stress test, 31P MR spectroscopy, and muscle biopsy mitochondria respiration and enzymological studies. These data should delineate any mitochondrial dysfunction in these patients and will permit the evaluation of two new non-invasive approaches for monitoring mitochondrial dysfunction: micro-organic breathe analysis and trans-muscular Near Infrared (NIR) spectroscopy. The micro-organic breathe test evaluates exhaled organic molecules using an ultra-sensitive chemical detection system capable of detecting 20 parts per quadrillion. This system has revealed a wide variety of new organic chemicals in human breathe which appear to track with the individual’s physiological state. For example, exhaled ethanol permits monitoring of serum glucose levels during glucose tolerance tests. The trans-muscular NIR spectroscopy system employs an advanced multiple laser diode array to interrogate the absorption wavelengths for oxygenation and deoxygenated hemoglobin and oxidized versus reduced cytochonre c oxidase. When combined with an exercise regime, this new technology promises to permit the rapid non-invasive assessment of mitochondrial dysfunction.
These new physiological and biochemical tools will be coupled with a series of new molecular genetic approaches to search for clinically relevant mitochondrial DNA (mtDNA) sequence variants in the Metabolic Syndrome. Two classes of genetic studies will be conducted: family studies involving multiple large Taipei, Taiwan pedigrees and case control studies involving a cohort of 500 patients and controls from Taipei. The pedigrees will first be screened for mtDNA mutations known to result in Metabolic Syndrome. Those pedigrees that are negative will be further evaluated for heteroplasmic mtDNA mutations by Surveyor Nuclease digestion of heteroduplexes and for homoplasmic mtDNA mutations by complete mtDNA sequencing coupled with haplogorup analysis. Putative mtDNA mutations will be confirmed by linking specific mitochondrial defects detected by MITOCHIP expression profiles and/or biochemical aberrations to mtDNA variants via cybrid transfer experiments. The role of ancient mtDNA adaptive polymorphisms in Metabolic Syndrome will also be tested using the 500 subject Taiwan Metabolic Syndrome cohort. A series of mtDNA haplogroup-specific single nucleotide polymorphisms (SNPs) will be examined for all 500 subjects. These will then be correlated with their Metabolic Syndrome phenotypes. Preliminary studies already suggest that certain mtDNA haplogorups might be associated with hypertension.
From our preliminary results we anticipate that we will be able to confirm that the Metabolic Syndrome is a mitochondrial disease, identify a number of mtDNA mutations associated with these diseases, and perfect some effective new approaches to assist with the diagnosis of these common problems. More importantly, these studies should suggest new avenues for the treatment of these epidemic diseases.