new research on brain energy in mood and psychotic disorders
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New Research on Brain Energy in
Mood and Psychotic DisordersBruce 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
NAMI-MA October 30, 2010
Relevant Financial Relationships:
None
Relevant Personal Relationships:
Many
Suzann Babb, M.S. Jin Kim, B.A.Tom Berry, B.A. Nick Lange, Sc.D.Brian Brennan, M.D. Eve Lewandowski. Ph.D. Anne Carpenter, Ph.D. David Logan, Ph.D.Anne Cataldo, Ph.D. Jeanne Lothrop, B.S.Bruce M. Cohen, M.D., Ph.D. Julie McCarthy, B.A.Diane Damez-Werno, B.A. Donna McPhie, Ph.D.Joe DePaola, B.A. Emily Mensale, B.A. Sarah Elmiligy, B.A. Beth Murphy, M.D., Ph.D.Laura Flynn, B.A. Dost Öngür, M.D., Ph.D. Brent Forester, M.D. Caitlin Ravichandran, Ph.D.Jennifer Gelda, B.A. Laura Sargent, B.A.Linda Hassinger, M.S. Jordan Smoller, M.D., Sc.D.Hannah Irving, B.A. Nancy Ye, Ph.D.
List of Investigators Working on Project
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
Energy production and brain disorders
Background:
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.
Seymour S. Kety, M.D.
Energy use of the brain changes little,
even in illness, except under extreme circumstances, such as
coma.
The brain maintains energy production within a narrow
margin.
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 OrganThe 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
Raichle & Mintun, 2006
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.
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:
GeneticIn vivo brain imagingPost mortem gene expressionPeripheral cell gene expressionCSF 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)
Magnification 1,000X
CONTROL BIPOLAR DISEASE
BD Brains Have More Smaller Mitochondria
Than Control Brains (p<0.03)BD
Control
Area in Square Microns
Nu
mb
er
of M
itoch
ond
ria
Mitochondrial Shape Abnormalities in
Post Mortem Brain TissueCONTROL 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
0
20,000
40,000
60,000
80,000
100,000
120,000
140,000
Control BD
Square Pixels
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 HealthyNo Treatment 1mM Li2+
Control
BD
Are There Abnormalities of Mitochondrial Shape in Peripheral Cells,
as Observed in Brain, in BD?
Spherical and Cup Shaped Mitochondria
in BD Fibroblasts
BD
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
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
HOWEVER:
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 formitochondrial form and function?
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.
Future Directions: Proteins
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
Healthy mitochondria can be isolated
from blood cells and might beused to replace dysfunctional mitochondria in damaged cells
Mitochondrial Transplantation
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.
To all my colleagues who worked, and keep working,
so hard and well on these projects.(Anne would be pleased.)
THANKS
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
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