It's All About the Mitochondria:

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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
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Mitochondria are Key Players in...
ATP

• Generation of
• Ion homeostasis
• Innate immune responses
• Production of reactive oxygen species (ROS)
• Programmed cell death (apoptosis)
• Adaptive thermogenesis

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Mitochondrial Structure
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Mitochondrial Structure
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When Mitochondria Go Bad...

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

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When Mitochondria Go Bad...
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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

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RX Spotlight

• Amiodarone
• Aspirin
• Metformin
• Haloperidol
• Statins
• Valproic acid
• Zidovudine

• Antibiotics (ex. chloramphenicol)
• Chemotherapeutic agents (ex. doxorubicin)
• Inhaled anesthetics (ex. halothane)
• Environmental toxins

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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
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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

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What's in the Pipeline?

• Nutritional modulation affected mitochondrial fxn
• Cyclosporin A, a permeability transition-pore
  desensitizer ? Mutations in mitochondrial
  permeability pore protein, Ullrich's congenital
  muscular dystrophy

• Idebenone (CoQ10 variant) ? Friedreich's ataxia,
  Leber's hereditary optic neuropathy
• Ketogenic diet ? epileptic seizures in children
  with electron transport chain disorders

approved for use
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Pharmaceutical Intervention
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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

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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.