For some time now, researchers have been aware that having mitochondrial disease is a strong risk factor for bipolar disorder (BD). One mitochondrial condition in particular, chronic progressive ophthaloplegia (CPEO), has been studied extensively.
In CPEO, the accumulation of partially-deleted mitochondrial DNA (mDNA) in the brain has been observed and appears to be associated with recurrent depression. Partially-deleted mDNA accumulation has also been noted in BD. Thus, it has been proposed that mitochondrial gene mutations, by disrupting effective functioning of the mitochondria and intracellular calcium signaling systems, may confer the risk of BD.
Mitochondrial gene mutations, by disrupting effective functioning of the mitochondria and intracellular calcium signaling systems, may confer the risk of BD
To develop an animal model to further investigate this hypothesis, a point mutation was introduced into the mitochondrial DNA polymerase gamma 1 (POLG1) gene, thereby bringing about accumulation of partially-deleted mDNA. (By lucky happenstance, it was then independently discovered that a mutation in POLG1 is the causative mutation for CPEO with comorbid depression!)
Behavioral phenotypes of mutant POLG1 transgenic female mice showed recurrent hypoactive periods over a one year observation period, suggesting to the researchers than the mice were undergoing depressive episodes. They found that lithium withdrawal could provoke depression in the mice and, to take it one step further, antidepressant medications appeared to alleviate their depressive symptoms. Thus, there appears to be a good candidate animal model for BD.
Dr Kato, a proponent of the mitochondrial dysfunction hypothesis in BD, described recent work in which, once again, the important role POLG1 plays in BD was illustrated.
Sequencing the exomes of 79 “trios” (mother, father, and BP offspring) revealed 71 new mutations which were predominantly in genes for calcium-binding proteins
He described a study in which the exomes of 79 trios (mother, father and BP offspring) were sequenced to uncover any de novo mutations. A total of 71 new mutations were found, most of which created non-functioning proteins, predominantly in genes for calcium-binding proteins. One patient received a POLG1 mutation from his mother who had major depression. Functional analyses are underway to find out if any other of the mutations discovered are causal of BP.
Resequencing of the POLG1 gene in 796 patients with BD and 767 controls in a case-control manner has also revealed interesting results. Mutant proteins were made and functional assays for all the POLG1 mutations discovered undertaken. Enrichment for mutations was noted in the BD population supporting further not only the role of POLG1 variants in the pathophysiology of BP and but also the role of mitochondria and calcium dysfunction associated with this condition.