Neuroinflammation and Mitochondrial Dysfunction Link Social Stress to Depression

Hollis, Fiona; Pope, Brittany S.; Gorman-Sandler, Erin; Wood, Susan K.

doi:10.1007/7854_2021_300

Cited by 30 publications

(15 citation statements)

References 177 publications

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“…Mitochondria are involved in regulating the stress response mitochondrial biology is tissue- and cell-specific, particularly in the immune system ( 51 ). Social stress is a risk factor for the development of MDD ( 52 ) and contributes to mitochondrial dysfunction, leading to inflammatory disturbances ( 53 ). One study of metabolomic signatures reported that mitochondrial oxidative phosphorylation (OXPHOS), morphology, and recycling were crucial elements of the stress response.…”

Section: Discussionmentioning

confidence: 99%

Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder

Gong

et al. 2023

Front. Neurol.

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BackgroundThe retrograde endocannabinoid (eCB) pathway is closely associated with the etiology of major depressive disorder (MDD) at both pathophysiological and genetic levels. This study aimed to investigate the potential role of genetic mutations in the eCB pathway and underlying mechanisms in Han Chinese patients with MDD.MethodsA total of 96 drug-naïve patients with first-episode MDD and 62 healthy controls (HCs) were recruited. Whole-exome sequencing was performed to identify the gene mutation profiles in patients with MDD. Results were filtered to focus on low-frequency variants and rare mutations (minor allele frequencies <0.05) related to depressive phenotypes. Enrichment analyses were performed for 146 selected genes to examine the pathways in which the most significant enrichment occurred. A protein–protein interaction (PPI) network analysis was performed to explore the biological functions of the eCB pathway. Finally, based on current literature, a preliminary analysis was conducted to explore the effect of genetic mutations on the function of this pathway.ResultsOur analysis identified 146 (15.02%) depression-related genetic mutations in patients with MDD when compared with HCs, and 37 of the mutations were enriched in the retrograde eCB signaling pathway. Seven hub genes in the eCB pathway were closely related to mitochondrial function, including Complex I genes (NDUFS4, NDUFV2, NDUFA2, NDUFA12, NDUFB11) and genes associated with protein (PARK7) and enzyme (DLD) function in the regulation of mitochondrial oxidative stress.ConclusionThese results indicate that genetic mutations in the retrograde eCB pathway represent potential etiological factors associated with the pathogenesis of MDD.

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Section: Discussionmentioning

confidence: 99%

Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder

Gong

et al. 2023

Front. Neurol.

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“…Further studies will be necessary to fully characterize the biomarker potential of TNF-α for PFC mitochondrial function and PPD. As cytokines can also act to disrupt mitochondrial function (Hollis et al, 2022) future studies that manipulate mitochondrial function will be needed to determine the precise role of PFC mitochondrial respiration in PPD-relevant behaviors and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Gestational stress decreases postpartum mitochondrial respiration in the prefrontal cortex of female rats

Gorman-Sandler

Robertson

Crawford

et al. 2022

Preprint

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Postpartum depression (PPD) is a major psychiatric complication of childbirth, affecting up to 20% of mothers, yet remains understudied. Mitochondria, dynamic organelles crucial for cell homeostasis and energy production, share links with many of the proposed mechanisms underlying PPD pathology. Brain mitochondrial function is affected by stress, a major risk factor for development of PPD, and is linked to anxiety-like and social behaviors. Considering the importance of mitochondria in regulating brain function and behavior, we hypothesized that mitochondrial dysfunction is associated with behavioral alterations in a chronic stress-induced rat model of PPD. Using a validated and translationally relevant chronic mild unpredictable stress paradigm during late gestation, we induced PPD-relevant behaviors in adult postpartum Wistar rats. In the mid-postpartum, we measured mitochondrial function in the prefrontal cortex (PFC) and nucleus accumbens (NAc) using high-resolution respirometry. We then measured protein expression of mitochondrial complex proteins and 4-hydroxynonenal (a marker of oxidative stress), and Th1/Th2 cytokine levels in PFC and plasma. We report novel findings that gestational stress decreased mitochondrial function in the PFC, but not the NAc of postpartum dams. However, in groups controlling for the effects of either stress or parity alone, no differences in mitochondrial respiration measured in either brain regions were observed compared to nulliparous controls. This decrease in PFC mitochondrial function in stressed dams was accompanied by negative behavioral consequences in the postpartum, complex-I specific deficits in protein expression, and increased Tumor Necrosis Factor alpha cytokine levels in plasma and PFC. Overall, we report an association between PFC mitochondrial respiration, PPD-relevant behaviors, and inflammation following gestational stress, highlighting a potential role for mitochondrial function in postpartum health.

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“…Studies have reported that inflammation negatively affects mitochondria, leading to excitotoxicity, oxidative stress, and energy deficit, and that dysfunctional mitochondria may drive or propagate the inflammatory response, thus creating a vicious cycle ( 78 ). Numerous basic studies in recent years have found that the onset of depression is associated with mitochondrial dysfunction in brain regions ( 79 , 80 ). Mitochondrial dysfunction includes reduced ATP synthesis, oxidative respiratory chain dysfunction, abnormal mitochondrial structure and excessive occurrence of apoptosis ( 81 ).…”

Section: Cyclo-oxygen-ase-2 Roles In the Pathogenesis Of Depressionmentioning

confidence: 99%

Biology of cyclooxygenase-2: An application in depression therapeutics

Han

Liao

et al. 2022

Front. Psychiatry

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Depressive Disorder is a common mood disorder or affective disorder that is dominated by depressed mood. It is characterized by a high incidence and recurrence. The onset of depression is related to genetic, biological and psychosocial factors. However, the pathogenesis is still unclear. In recent years, there has been an increasing amount of research on the inflammatory hypothesis of depression, in which cyclo-oxygen-ase 2 (COX-2), a pro-inflammatory cytokine, is closely associated with depression. A variety of chemical drugs and natural products have been found to exert therapeutic effects by modulating COX-2 levels. This paper summarizes the relationship between COX-2 and depression in terms of neuroinflammation, intestinal flora, neurotransmitters, HPA axis, mitochondrial dysfunction and hippocampal neuronal damage, which can provide a reference for further preventive control, clinical treatment and scientific research on depression.

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Neuroinflammation and Mitochondrial Dysfunction Link Social Stress to Depression

Cited by 30 publications

References 177 publications

Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder

Genetic variations in the retrograde endocannabinoid signaling pathway in Chinese patients with major depressive disorder

Gestational stress decreases postpartum mitochondrial respiration in the prefrontal cortex of female rats

Biology of cyclooxygenase-2: An application in depression therapeutics

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