Major Depressive Disorder is Associated with Impaired Mitochondrial Function in Skin Fibroblasts

Abstract

Mitochondrial malfunction is supposed to be involved in the etiology and pathology of major depressive disorder (MDD). Here, we aimed to identify and characterize the molecular pathomechanisms related to mitochondrial disfunction in adult human skin fibroblasts which were derived from MDD patients or non-depressive control subjects. We found that MDD fibroblasts showed significantly impaired mitochondrial functioning: basal and maximal respiration, spare respiratory capacity, non-mitochondrial respiration and ATP-related oxygen consumption was lower. Moreover, MDD fibroblasts harbor lower ATP levels and showed hyperpolarized mitochondrial membrane potential. To investigate cellular resilience, we challenged both groups of fibroblasts with hormonal (dexamethasone) or metabolic (galactose) stress for one week, and found that both stressors increased oxygen consumption but lowered ATP content in MDD as well as in non-depressive control fibroblasts. Interestingly, the bioenergetic differences between fibroblasts from MDD or non-depressed subjects, which were observed under non-treated conditions, could not be detected after stress. Our findings support the hypothesis that altered mitochondrial function causes a bioenergetic imbalance which is associated with the molecular pathophysiology of MDD. The observed alterations in OXPHOS and other mitochondria-related properties represent a basis for further investigations of pathophysiological mechanisms and might open new ways to gain insight into antidepressant signaling pathways.

Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties

“…As a measure of mitochondrial function/dysfunction we measured the ATPcontent, the mitochondrial membrane potential (MMP), the mitochondrial oxidative phosphorylation system (OXPHOS), and the cytosolic Ca 2+ homeostasis in NPCs of depressed patients (MDD) and compared these parameters to non-depressed controls. Interestingly, the reprogrammed NPCs presented functional alterations, which might be associated with bioenergetic dysfunction of mitochondria in MDD patient cells and were in line with findings obtained in the founder fibroblasts (1).…”

“…This functional phenotype indicates a significant mitochondrial dysfunction which was already evident in the original cells (i.e. fibroblasts) of depressed patients (1). Other functional parameters of the bioenergetic status of the NPCs such as the maximal respiration, cellular ATP content or cytosolic Ca 2+ level were not found to be significantly different between the MDD and the control group, although the cytosolic was not certified by peer review) is the author/funder.…”

“…Moreover, the fact that therapeutic approaches using common antidepressants often show insufficient efficacy and low response rates, strengthens the need for deeper investigation of involved mechanisms. In order to identify and characterize molecular pathomechanisms of depression, we established a human cellular model, which is based on dermal fibroblasts derived from skin biopsies of depressed patients and non-depressed controls (1). In detail, we used induced pluripotent stem cell-derived neural progenitor cells reprogrammed from the skin fibroblasts to investigate cellular and molecular function of depressed cells and focused on possible bioenergetic differences in NPC which might be associated with depressive syndrome.…”

“…Since NPCs rely mostly on their glycolytic activity for ATP production (20,21), they cannot survive under such a metabolic stress. Thus, when testing for cellular resilience of MDD and control NPCs, we challenged the cells with dexamethasone to apply hormonal stress on mitochondrial function only, but refrained from metabolic stress, which we additionally used for characterization of fibroblasts (1). Interestingly, differences in mitochondrial function between MDD and control groups vanished upon the treatment of NPCs with dexamethasone, demonstrating that mitochondrial respiration and function in depressed and non-depressed cells reached similar levels under hormonal stress.…”

“…Human primary skin fibroblasts derived from 8 depressed patients and 8 non-depressed controls (1) were reprogrammed to iPSCs and differentiated to NPCs using established media, supplements and protocols from STEMCELL Technologies and Life Technologies (see SUPPLEMENTAL METHODS AND MATERIALS). Pluripotency of the iPSCs was analyzed using PluriTest® method (18).…”