Mitochondrial and cellular function in fibroblasts and reprogrammed neural cells: insights into major depression as a mitochondria-associated disease

Abstract The neurobiological underpinnings of major depressive disorder (MDD) remain still elusive. Meanwhile, mitochondria and energy metabolism turn into focus as relevant pathomechanisms of MDD. To gain further insight on the role of mitochondria function in MDD, in the present work, we examined the functional cellular and mitochondrial properties in cells derived from two specific patients, diagnosed as suffering from a mild form of mitochondriopathy with unknown cause, and an antidepressant non-responding MDD patient and compared these patients to a cohort of MDD and control subjects. Using skin biopsies of the two patients as well as non-depressed healthy controls, we obtained dermal fibroblasts and generated iPSCs, neural progenitors, neurons, and astrocytes. Notably, we observed that cellular and mitochondrial functions and neuronal electrophysiology in the mitochondriopathy patient resembled findings in the MDD cohort. This included decreased respiration, mitochondrial membrane potential (MMP) and depolarized resting membrane potential, associated with smaller sodium currents. In contrast, cells derived from the non-responder MDD patient were affected in an opposite manner in many of the measured parameters, including increased respiratory rates, mitochondrial calcium, and lower resting membrane potential. However, in all patient cells we consistently observed a smaller cell size compared to healthy controls. Our findings revealed marked similarities between the mitochondriopathy patient and the MDD cohort, supporting the hypothesis that mitochondria play a significant role in the pathophysiology of depression. The overall opposite functional phenotype of the non-responder patient pointed towards distinct or counterregulatory mechanisms involved in the etiology and/or treatment resistance of depression in this patient and emphasized the importance of investigating depression-related phenotypes from different disease entities to gain a more comprehensive understanding of the pathology of MDD.