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
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
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
• Antibiotics (ex.
chloramphenicol)
• Chemotherapeutic
agents (ex.
doxorubicin)

Metformin

Haloperidol

Statins

Valproic acid
• Inhaled anesthetics
(ex. halothane)

Zidovudine
• 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
ADME
properties of
•
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
*approved for use
• Nutritional modulation
affected mitochondrial
fxn
• Cyclosporin A, a
permeability transitionpore desensitizer →
Mutations in
mitochondrial
permeability pore
protein, Ullrich's
congenital muscular
dystrophy
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.