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.
Highlights
Reviewed by: Carmen Sandi, École Polytechnique Fédérale de Lausanne, Switzerland Sandeep Kumar Barodia, The University of Alabama at Birmingham, United States
We summarize some of the latest knowledge on mitochondrial dysregulation in major depression and discuss how mitochondrial dysfunction could instigate downstream changes in extracellular matrix proteins such as reelin, neuronal nitric oxide, oxidative stress, and inflammation, and adult hippocampal neurogenesis
Less direct evidence comes from observations that mice with mutations of the POLG gene, which encodes a subunit of mitochondrial DNA (mtDNA) polymerase, exhibit depression-like symptoms (Kasahara et al, 2006), and that polymorphisms of genes that code for mitochondrial enzymes, such as MTHFD1L, are associated with negative rumination, which is a precursor to depression (Eszlari et al, 2016)
Summary
The focus of this review is the link between mitochondrial dysfunction and major depression. We summarize some of the latest knowledge on mitochondrial dysregulation in major depression (depicted in Figure 1) and discuss how mitochondrial dysfunction could instigate downstream changes in extracellular matrix proteins such as reelin, neuronal nitric oxide (nNOS), oxidative stress, and inflammation, and adult hippocampal neurogenesis. Uncovering how all these factors influence one another could lead to new vistas in the development of novel therapeutics for the treatment of this problematic disorder
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