Mitochondria and Mood: Mitochondrial Dysfunction as a Key Player in the Manifestation of Depression

Abstract

Human and animal studies suggest an intriguing link between mitochondrial diseases and depression. Although depression has historically been linked to alterations in monoaminergic pharmacology and adult hippocampal neurogenesis, new data increasingly implicate broader forms of dampened plasticity, including plasticity within the cell. Mitochondria are the cellular powerhouse of eukaryotic cells, and they also regulate brain function through oxidative stress and apoptosis. In this paper, we make the case that mitochondrial dysfunction could play an important role in the pathophysiology of depression. Alterations in mitochondrial functions such as oxidative phosphorylation (OXPHOS) and membrane polarity, which increase oxidative stress and apoptosis, may precede the development of depressive symptoms. However, the data in relation to antidepressant drug effects are contradictory: some studies reveal they have no effect on mitochondrial function or even potentiate dysfunction, whereas other studies show more beneficial effects. Overall, the data suggest an intriguing link between mitochondrial function and depression that warrants further investigation. Mitochondria could be targeted in the development of novel antidepressant drugs, and specific forms of mitochondrial dysfunction could be identified as biomarkers to personalize treatment and aid in early diagnosis by differentiating between disorders with overlapping symptoms.

Keywords: antidepressants; behavior; depression; mitochondria; oxidative phosphorylation; reelin.

FIGURE 1

The mitochondrion under normal physiological conditions and in the depression brain. As detailed in the right side of the image, there are a series of mitochondrial alterations that have been observed both in depressed patients and in animal models of depression (red lines). These include changes affecting mitochondrial DNA, membrane permeability, and increased formation of reactive oxygen species (ROS). As a consequence, these alterations lead to pro-inflammatory activity, increased apoptosis, and dampened synaptic plasticity and neuronal differentiation. Interestingly, antidepressant medication can restore the mitochondrial oxidant/antioxidant balance, and therefore help to rescue the negative effects of mitochondrial dysregulation (green lines). See the text for more detailed explanations.