Severe life stress, mitochondrial dysfunction, and depressive behavior: A pathophysiological and therapeutic perspective

Allen, Josh; Caruncho, Héctor J.; Kalynchuk, Lisa E.

doi:10.1016/j.mito.2020.11.010

Cited by 35 publications

(35 citation statements)

References 110 publications

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“…However, the precise regulatory roles that histone H3 and H4 proteins provide independently to the overall oxidative stress response remain unclear and warrants further investigation. Mitochondrial dysfunction and the accumulation of oxidative stress are crucial factors in the pathophysiology of MDD[ 57 - 59 ], and biomarkers of oxidative stress are elevated in drug-naïve first episode SZ patients[ 60 ]. Thus, there is strong interest in targeting oxidative stress deficiencies in MDD, BP and SZ[ 61 ] through antioxidant treatments such as N-acetylcysteine[ 62 ].…”

Section: Epigenetic Modifications Identified By Transgenerational Studies Of C Elegans Relevant To Psychiatrymentioning

confidence: 99%

Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man

Hime¹,

Stonehouse²,

Pang³

2021

WJP

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Mental illness remains the greatest chronic health burden globally with few in-roads having been made despite significant advances in genomic knowledge in recent decades. The field of psychiatry is constantly challenged to bring new approaches and tools to address and treat the needs of vulnerable individuals and subpopulations, and that has to be supported by a continuous growth in knowledge. The majority of neuropsychiatric symptoms reflect complex gene-environment interactions, with epigenetics bridging the gap between genetic susceptibility and environmental stressors that trigger disease onset and drive the advancement of symptoms. It has more recently been demonstrated in preclinical models that epigenetics underpins the transgenerational inheritance of stress-related behavioural phenotypes in both paternal and maternal lineages, providing further supporting evidence for heritability in humans. However, unbiased prospective studies of this nature are practically impossible to conduct in humans so preclinical models remain our best option for researching the molecular pathophysiologies underlying many neuropsychiatric conditions. While rodents will remain the dominant model system for preclinical studies (especially for addressing complex behavioural phenotypes), there is scope to expand current research of the molecular and epigenetic pathologies by using invertebrate models. Here, we will discuss the utility and advantages of two alternative model organisms– Caenorhabditis elegans and Drosophila melanogaster –and summarise the compelling insights of the epigenetic regulation of transgenerational inheritance that are potentially relevant to human psychiatry.

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Section: Epigenetic Modifications Identified By Transgenerational Studies Of C Elegans Relevant To Psychiatrymentioning

confidence: 99%

Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man

Hime¹,

Stonehouse²,

Pang³

2021

WJP

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“…Alterations in mitochondrial function and biogenesis have been established to be critical factors in MDD pathophysiology (87)(88)(89)(90). These factors are also regulated during hypoxic conditions through HIFs (91,92).…”

Section: Disturbances In Mitochondrial Function and Biogenesis During Hypoxic Conditions And Major Depressive Disordermentioning

confidence: 99%

Oxygen - Mitochondrial fuel as a missing link in depressive pathophysiology

Mavioğlu¹,

Mack²,

Behnke³

et al. 2021

Preprint

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Major depressive disorder (MDD) causes enormous individual suffering and socioeconomic costs. Biochemical mechanisms leading to MDD are poorly understood and therapy success is not satisfactory. At present, there is evidence of low-grade inflammation, oxidative stress, and most interestingly, a disturbed energy metabolism in MDD and other mental health diseases. Mitochondria play a central part in energy production and stress signaling. Mitochondrial electron transport chain uses molecular oxygen (O2) as final electron acceptor during adenosine triphosphate production attributing a crucial role to an intact O2 supply. Adaptation to altered O2 availability by the highly conserved hypoxic response is essential for maintaining allostasis. Previous research confirmed the role of O2 metabolism in the pathophysiology of MDD. In this perspective article, we compile the evidence linking O2 transport, O2 homeostasis, and mitochondrial energy metabolism to MDD. Furthermore, we hypothesize that inflammation and oxidative stress-related alterations in O2 transport might lead to a hypoxic response, which explains changes in O2 homeostasis and energy metabolism in MDD. Our forthcoming studies will investigate the interplay between energy metabolism and O2 homeostasis in MDD that aim to improve the overall understanding of the pathophysiology of MDD and to guide medical and psychological diagnostics towards a holistic strategy.

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“…Mitochondria are intracellular organelles that generate most of the chemical energy needed to power biochemical reactions of the cell. According to recent theories, they also seem to play a key role in the pathological stress response ( Morava and Kozicz, 2013 ; Daniels et al, 2020 ; Allen et al, 2021 ). As described by the “mitochondrial allostatic load” theory, chronic stress disrupts the glucocorticoid and glucose homeostasis which in turn alter mitochondrial structure and function ( Picard et al, 2014 , 2018 ).…”

Section: Introductionmentioning

confidence: 99%

A Preliminary Quantitative Electron Microscopic Analysis Reveals Reduced Number of Mitochondria in the Infralimbic Cortex of Rats Exposed to Chronic Mild Stress

Csabai

Sebők-Tornai

Wiborg

et al. 2022

Front. Behav. Neurosci.

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Exposure to severe, uncontrollable and long-lasting stress is a strong risk factor for the development of numerous mental and somatic disorders. Animal studies document that chronic stress can alter neuronal morphology and functioning in limbic brain structures such as the prefrontal cortex. Mitochondria are intracellular powerhouses generating chemical energy for biochemical reactions of the cell. Recent findings document that chronic stress can lead to changes in mitochondrial function and metabolism. Here, we studied putative mitochondrial damage in response to chronic stress in neurons of the medial prefrontal cortex. We performed a systematic quantitative ultrastructural analysis to examine the consequences of 9-weeks of chronic mild stress on mitochondria number and morphology in the infralimbic cortex of adult male rats. In this preliminary study, we analyzed 4,250 electron microscopic images and 67000 mitochondria were counted and examined in the brains of 4 control and 4 stressed rats. We found significantly reduced number of mitochondria in the infralimbic cortex of the stressed animals, but we could not detect any significant alteration in mitochondrial morphology. These data support the concept that prolonged stress can lead to mitochondrial loss. This in turn may result in impaired energy production. Reduced cellular energy may sensitize the neurons to additional injuries and may eventually trigger the development of psychopathologies.

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Severe life stress, mitochondrial dysfunction, and depressive behavior: A pathophysiological and therapeutic perspective

Cited by 35 publications

References 110 publications

Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man

Alternative models for transgenerational epigenetic inheritance: Molecular psychiatry beyond mice and man

Oxygen - Mitochondrial fuel as a missing link in depressive pathophysiology

A Preliminary Quantitative Electron Microscopic Analysis Reveals Reduced Number of Mitochondria in the Infralimbic Cortex of Rats Exposed to Chronic Mild Stress

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