NAMI-MA October 30, 2010
New Research on Brain Energy in
Mood and Psychotic Disorders
Bruce M. Cohen, M.D., Ph.D.
Director, Shervert Frazier Research Institute, McLean Hospital
President and Psychiatrist in Chief Emeritus, McLean Hospital
Robertson-Steele Professor of Psychiatry, Harvard Medical School
Relevant Financial Relationships:
None
Relevant Personal Relationships:
Many
List of Investigators Working on Project
Suzann Babb, M.S.
Tom Berry, B.A.
Brian Brennan, M.D.
Anne Carpenter, Ph.D.
Anne Cataldo, Ph.D.
Bruce M. Cohen, M.D., Ph.D.
Diane Damez-Werno, B.A.
Joe DePaola, B.A.
Sarah Elmiligy, B.A.
Laura Flynn, B.A.
Brent Forester, M.D.
Jennifer Gelda, B.A.
Linda Hassinger, M.S.
Hannah Irving, B.A.
Jin Kim, B.A.
Nick Lange, Sc.D.
Eve Lewandowski. Ph.D.
David Logan, Ph.D.
Jeanne Lothrop, B.S.
Julie McCarthy, B.A.
Donna McPhie, Ph.D.
Emily Mensale, B.A.
Beth Murphy, M.D., Ph.D.
Dost Öngür, M.D., Ph.D.
Caitlin Ravichandran, Ph.D.
Laura Sargent, B.A.
Jordan Smoller, M.D., Sc.D.
Nancy Ye, Ph.D.
A Caveat:
Bipolar disorders and other psychiatric
disorders are not homogeneous or unitary
by cause or pathophysiology.
They are likely the consequence of the
interaction of numerous factors, both
inherited and environmental, which differ
from person to person.
Problems in energy production
may be one factor contributing
to the risk of developing bipolar
or other brain disorders
Background:
Energy production and brain disorders
Blood Flow and Metabolism of the
Human Brain in Health and Disease
Seymour S. Kety, M.D.
“The blood flow of the brain
represents about one-sixth of the
cardiac output and its oxygen
consumption nearly one quarter of that
of the entire body.”
Trans Stud Coll Physicians Phila. 1950 Dec;18:103-8.
The brain maintains energy
production within a narrow margin.
Energy use of the brain changes little,
even in illness, except under extreme
circumstances, such as coma.
Seymour S. Kety, M.D.
The brain uses ten times more energy per
unit weight than the rest of the body
Even subtle abnormalities of energy
metabolism can affect brain function
Energy abnormalities have been observed
in many disorders of the brain
Why Is the Brain
So Energy Dependent?
The Brain is a High-Precision
Electro-Chemical Organ
The brain must not only generate, but must
quite accurately control,
numerous electrical and chemical signals.
Each of these tasks is highly
energy expensive, and the energy must be
made close to where it is used.
Pellerin and Magistretti, Science 2004
Nearly 99% of the energy production of
the brain is used to support intrinsic
(resting) activity. It is energy expensive
just to support the basic background state
and maintenance work of the brain.
Raichle & Mintun, 2006
Where Does the Brain
Get Its Energy?
Most of the energy produced to support
the work of the brain comes from
oxidative phosphorylation, the complete
‘burning’ (oxidation) of glucose (sugar)
to carbon dioxide and water.
Oxidative phosphorylation occurs in,
and only in, subcellular organelles
called mitochondria.
Energy Production and
Bipolar Disorders
A variety of early studies, including:
Genetic
In vivo brain imaging
Post mortem gene expression
Peripheral cell gene expression
CSF metabolite studies
All suggest abnormalities of energy
metabolism in patients with bipolar disorder
We looked directly at mitochondria
of patients with bipolar disorders.
We studied both brain and
peripheral cells from public tissue banks.
Mitochondrial Distribution in Brain Cells
(Post Mortem-Cytochrome C Staining)
CONTROL
BIPOLAR DISEASE
Magnification 1,000X
BD Brains Have More Smaller Mitochondria
Than Control Brains (p<0.03)
Number of Mitochondria
BD
Control
Area in Square Microns
Mitochondrial Shape Abnormalities in
Post Mortem Brain Tissue
CONTROL
BIPOLAR DISORDER
EM Magnification 15,000X
Can We See Abnormalities
in Peripheral Cells?
Is There an Abnormality of
Mitochondrial Distribution in Peripheral
Cells, as Observed in Brain, in BD?
Mitochondria Look Abnormal in Fibroblasts
from Patients with Bipolar Disorder
Mitochondria from fibroblasts in patients with bipolar disorder
show an altered morphology consisting of short, thickened
profiles that are arranged in a predominantly perinuclear
location compared to age-matched controls.
Mitochondrial Network in Control
and BD Lymphocytes
Light Microscopy Magnification 1,000X
Quantification of Mitochondrial
Distribution in Fibroblasts
Quantification of Changes in
Mitochondrial Distribution
BD vs. Control, p<0.0008
Are there more or fewer
mitochondria in BD?
No Difference in Total Mitochondrial Area Between
Bipolar Disorder and Control Fibroblasts
140,000
Square Pixels
120,000
100,000
80,000
60,000
40,000
20,000
0
Control
BD
Is the Difference in Distribution of
Mitochondria in BD a Drug Effect?
(There was a wide assortment of drugs taken by the
subjects. Lithium was used by only half, and its use
was not correlated with the mitochondrial
abnormalities observed.)
Lithium Does Not Make Healthy Subject’s Cells
Look Sick or BD Cells Look Healthy
No Treatment
Control
BD
1mM Li2+
Are There Abnormalities of
Mitochondrial Shape in Peripheral Cells,
as Observed in Brain, in BD?
Spherical and Cup Shaped Mitochondria
in BD Fibroblasts
B
D
Magnification
1,000X
EM Magnification
10,000X
Quantification of Ring Shaped Mitochondria
in Control and BD Fibroblasts
• Ultrastructural images from thirty fibroblasts were
obtained at random (magnification 10,000X by
electron microscopy) from each of 4 healthy
controls and 4 BD cell lines (in total, 120 controls
fibroblasts and 120 BD fibroblasts).
• We found that the number of ring structures was
increased in cells from the BD patients compared to
controls (Controls<1, BD>1, per cell, p<0.01).
Is There a Functional Abnormality
of Mitochondria in Peripheral
Cells in Bipolar Disorder?
Mitochondrial Membrane Potential Staining
(JC1) in Control and BD Fibroblasts
CONTROL
BIPOLAR DISEASE
Red = Healthy Mitochondria
Green = Compromised Mitochondria with lower membrane potential
Are These Abnormalities
Specific to BD?
Schizophrenic Patient’s Fibroblasts May Exhibit
Distinct Mitochondrial Abnormalities
Control
Bipolar Disorder
Schizophrenia
Magnification 630X
HOWEVER:
While consistent and from multiple
sources, all of the evidence for
abnormalities of energy production or
mitochondrial shape and location in
bipolar or related disorders is subtle,
preliminary and needs confirmation
Future Directions: Much More To Do
By computerized analyses, we are determining
many features of the shape and distribution
of the mitochondrial network in our samples.
With electron microscopy, we have begun to look
at individual mitochondria in our samples.
We are studying mitochondrial function at McLean
and in collaboration with local colleagues.
Future Directions: Genetics
The risk of psychiatric illnesses is
highly determined by genetic factors.
Given our findings, might some of the
genes associated with bipolar disorders
and schizophrenias be genes for
mitochondrial form and function?
Future Directions: Proteins
Many diseases are associated with
abnormal levels or activities of the
proteins which perform cell functions.
We have begun to look directly at proteins
known to be involved in determining
mitochondrial location, shape and activity.
MITOCHONDRIAL
MORPHOLOGICAL
ABNORMALITIES
DYSREGULATION OF FUSION
AND FISSION PROTEINS, WHICH
CONTROL MITOCHONDRIAL
SHAPE, e.g. DRP1, ORA1
DYSREGULATION OF MOTOR
PROTEINS, WHICH MOVE
MITOCHONDRIA IN THE CELL,
e.g .MIRO, MISATO, MYOSIN V
DYSREGULATION OF
CYTOSKELETAL PROTEINS,
TO WHICH
MITOCHONDRIA ATTACH,
e.g. ACTIN, TUBULIN
There are no Large Scale Changes
in the Actin Cytoskeleton in BD
Green = Mitochondria Red = Actin
Blue = Nuclei
No Overall Changes are Seen in
the Tubulin Cytoskeleton in BD
Control
BD
Red/Orange = mitochondria Green = Tubulin
Clinical trials: We are testing agents
believed to increase mitochondrial function
Brian Brennan et al Acetyl-L-carnitine and alpha lipoic acid
for bipolar depression
Brent Forrester et al Coenzyme Q10 for geriatric bipolar depression
Can mitochondria be
repaired or replaced?
Some Developing Technologies
for Neurorepair
Gene Alteration
Nanomedicine
Organelle Replacement / Repair
Cell Replacement / Repair
Biofeedback and Cognitive Training
Mitochondrial Transplantation
Healthy mitochondria can be isolated
from blood cells and might be
used to replace dysfunctional
mitochondria in damaged cells
The Meaning of Our Results
Abnormalities of mitochondrial form,
distribution and function may be important
factors in determining risk for mood and
psychotic disorders.
If so, we should be able to identify the causes
of those mitochondrial abnormalities and use
that knowledge to design better treatments and
preventive measures for psychiatric illnesses.
THANKS
To all my colleagues who worked, and keep working,
so hard and well on these projects.
(Anne would be pleased.)
To NAMI, for all it’s work to improve lives,
advance knowledge and improve our society.
Good science and good lives are collaborations.
Art and Science: The Paintings
of Lynda Cutrell