It's All About the Mitochondria:“Monogenic Mitochondrial Disorders”

→ NEJM, March 2012

George Ngo, PharmD CandidateApril 6, 2012University of Georgia College of PharmacyClass of 2012

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

Mitochondrial Structure

Mitochondrial Structure

When Mitochondria Go Bad...

Alzheimer's disease Parkinson's disease Cancer Cardiac disease Diabetes Epilepsy Huntington's disease Obesity

When Mitochondria Go Bad...

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

RX Spotlight

Amiodarone Aspirin Metformin Haloperidol Statins Valproic acid Zidovudine

• Antibiotics (ex. chloramphenicol)

• Chemotherapeutic agents (ex. doxorubicin)

• Inhaled anesthetics (ex. halothane)

• Environmental toxins

“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

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

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

Pharmaceutical Intervention

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

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.