On the role of mitochondrial dysfunction in the molecular pathology of major depressive disorder

Abstract

The molecular etiology of major depressive disorder (MDD) is still not exactly known. We believe today that a combination of genetic, neurobiological and psychosocial factors lead to cellular/molecular dysfunction and increase the vulnerability of neuronal and other somatic cells. Additional stress contribute to the etiology of MDD promoting the development of the disease. Neurobiological factors include monoaminergic, glutamatergic and GABAergic neurotransmitter systems as well as the involvement of the immune system and neurotrophic factors. The dysregulation of neurogenesis, apoptosis and neuronal plasticity as well as mitochondrial dysfunction are factors shown to play significant roles in the pathology of MDD. Based on the hypothesis that MDD could be caused by mitochondrial dysfunction, we set out to identify and characterize molecular pathomechanisms in cells derived from depressed patients. To establish a human cellular model of depression, we obtained skin fibroblast biopsies from depressed patients and gender and age matched healthy controls. Using the fluorescent cationic dyes JC-1 and TMRE, we found the mitochondrial membrane potential to be significantly depolarized in MDD fibroblasts. The depolarized mitochondrial membrane potential indicates a bioenergetic disbalance probably as consequence of mitochondrial dysfunction reflecting the hypometabolism associated with MDD. Deeper investigation of underlying molecular mechanisms will follow.