MITOCHONDRIAL DYSFUNCTION IN BIPOLAR DISORDER

Tadafumi

Laboratory for Molecular Dynamics of Mental Disorders, Brain Science Institute,

We

previously reported that energy metabolism was altered in the frontal lobes in

patients with bipolar disorder using phosphorus magnetic resonance spectroscopy

(³¹P-MRS).  Recently, we found that decreased intracellular pH was

confirmed in the non-localized ³¹P-MR spectra of eh head, suggesting

that altered intracellular pH reflected the alteration of cellular metabolism in

bipolar disorder.  Among the ³¹P-MRS findings of bipolar disorder,

significantly enhanced response of phosphocreatine (PCr) after the photic

stimulation in the occipital cortex was also reported in patients with

mitochondrial myopathy (chronic progressive external ophthalmoplegia, CPEO)

without central nervous system involvement.   CPEO is caused by deletion of

mitochondrial DNA (mtDNA).  There are three types of autosomal dominantly

inherited CPEO caused by mutations of POLG, ANT1, and Twinkle, all of which are

accompanied by depression or bipolar disorder.  In addition, patients with

Wolfram disease, frequently accompanies bipolar disorder also have multiple

deletions of mtDNA in the brain.  These findings altogether suggested that

bipolar disorder is related to mitochondrial dysfunction caused by accumulation

We are

not studying the role of mitochondrial dysfunction in bipolar disorders using

several approaches.  1) Analysis of calcium signaling, mitochondrial membrane

potential, and complex I activity of transmitochondrial cybrids established from

platelets of bipolar disorder patients.  2) Association and gene expression

analysis of nuclear encoded mitochondrial complex I subunit genes. 3) Generation

of transgenic mice accumulating multiple deletion s of mtDNA. 4) Analysis of

whole mtDNA sequence in patients with bipolar disorder. 5) Quantification of

multiple deletions in the postmortem brains and lymphocytes.  The preliminary

results of these studies confirmed our hypothesis that bipolar disorder is