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.

Severe hydroxymethylbilane synthase deficiency causes depression-like behavior and mitochondrial dysfunction in a mouse model of homozygous dominant acute intermittent porphyria

“…Aberrant mitochondrial function is increasingly recognized as an important element in the pathophysiological mechanisms of depression (for review see [59]) and physiological mitochondrial activity is pivotal for oligodendrocyte function and myelin production [67,68]. These considerations close the loop to the affective and myelination deficits in KI mice and collectively suggest compromised mitochondrial function as pathogenetic mechanism contributing to the behavioral and neuropathological manifestations in the HMBS-deficient mouse model of HD-AIP ( Fig.…”

“…Disturbed mitochondrial energy production is frequently observed in congenital diseases and often related to neurological and psychiatric symptoms [58,59]. Taking into consideration that half of the heme biosynthetic pathway is processed in the mitochondria and that disturbed heme metabolism causes mitochondrial defects [50,51], a possible direct link between AIP and mitochondrial dysfunction is plausible.…”

Mood‐related central and peripheral clocks

“…This makes the brain highly vulnerable to changes in mitochondrial function or antioxidant production. Indeed, several studies have linked mitochondrial dysfunction to psychiatric disorders including bipolar disorder, schizophrenia, and major depression (Allen, Romay‐Tallon, Brymer, Caruncho, & Kalynchuk, ; Clay, Sillivan, & Konradi, ; Manji et al., ; Marazziti et al., ). In turn, patients with mitochondrial diseases often display symptoms which are characteristic of psychiatric disorders.…”

REM sleep: unique associations with behavior, corticosterone regulation and apoptotic pathways in chronic stress in mice

“…They included pathways playing a role in oxidative stress or apoptosis with the pathway involved in the transport of proapoptic proteins linking the Jun amino-terminal kinases (JNK) signal transduction pathway and the mitochondrial apoptotic machinery (86). A causal role for mitochondrial genes was recently proposed as part of the processes in the striatum linking REMS parameters and stressinduced anxiety-like phenotype (75) and the contribution of mitochondrial dysfunction in major depression is emerging (87).…”