1. It's All About the Mitochondria: “Monogenic Mitochondrial Disorders” → NEJM, March 2012 George Ngo, PharmD Candidate April 6, 2012 University of Georgia College of Pharmacy Class of 2012

2. Mitochondria are Key Players in... Generation of Ion homeostasis Innate immune responses Production of reactive oxygen species (ROS) Programmed cell death (apoptosis) Adaptive thermogenesis ATP

3. Mitochondrial Structure

5. When Mitochondria Go Bad... Alzheimer's disease Parkinson's disease Cancer Cardiac disease Diabetes Epilepsy Huntington's disease Obesity

6. When Mitochondria Go Bad...

7. Why Should We Care? Progressive decline in the expression of mitochondrial genes is a central feature of normal human aging It is unclear whether changes the mitochondrial genetic expression has positive or negative effects on life span The aging of the population in developed societies and prevalence of previously mentioned diseases

8. RX Spotlight Amiodarone Aspirin Metformin Haloperidol Statins Valproic acid Zidovudine Antibiotics (ex. chloramphenicol) Chemotherapeutic agents (ex. doxorubicin) Inhaled anesthetics (ex. halothane) Environmental toxins

9. “Mitochondrial Medicine” Certain pts with mitochondrial disorders may be at higher risk of developing adverse reactions / side effects than healthy pts Mitochondrial dysfunction can be one MOA of new drugs New drugs are being studied in terms of: time and concentration at the cellular / mitochondrial level structure-activity relationships properties of ADME

10. Pharmaceutical Intervention There are four strategies for intervening in mitochondrial dysfunction  Genetic therapy  Small molecules to target specific cellular sites  Metabolic manipulation  Diet and exercise

11. What's in the Pipeline? Idebenone (CoQ10 variant) → Friedreich's ataxia*, Leber's hereditary optic neuropathy Ketogenic diet → epileptic seizures in children with electron transport chain disorders Nutritional modulation affected mitochondrial fxn Cyclosporin A, a permeability transition- pore desensitizer → Mutations in mitochondrial permeability pore protein, Ullrich's congenital muscular dystrophy *approved for use

12. Pharmaceutical Intervention

13. More Mitochondria Involved... Cyclosporin A → decreased size of myocardial infarcts during cardiac reperfusion Nutritional therapy → diabetes Pioglitazone → diabetes Human growth hormone → obesity Vitamin E → mitochondrial trifunctional protein deficiency

14. References Koopman WJ, Willems PH, Smeitlink JA. "Monogenic Mitochondrial Disorders." The New England Journal Of Medicine 366.12 (2012): 1132-41. MEDLINE with Full Text. Web. 06 April 2012.