Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1α axis

Fanibunda, Sashaina E.; Deb, Sukrita; Maniyadath, Babukrishna; Gupta, Samir; Weisstaub, Noelia V.; Gingrich, Jay A.; Vaidya, Ashok D.B.; Kolthur‐Seetharam, Ullas; Vaidya, Vidita A.

doi:10.1101/497982

Cited by 9 publications

(14 citation statements)

References 17 publications

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“…Serotonin coevolved with mitochondria, once free-living endosymbiotic organelles that generate most of the chemical energy that fuels the cell's biochemical reactions (Picard, McEwen, Epel, & Sandi, 2018). Serotonin (like the other biogenic amines dopamine and norepinephrine) is a very ancient neurotransmitter with cell bodies buried deep in the brain stem (it has been around a long time in evolutionary terms) and plays a key role in mitochondrial biogenesis (Fanibunda et al, 2019).…”

Section: Depression As An Evolved Adaptationmentioning

confidence: 99%

Is cognitive therapy enduring or antidepressant medications iatrogenic? Depression as an evolved adaptation.

Hollon¹

2020

American Psychologist

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Patients treated to remission with cognitive therapy are less than half as likely to relapse following treatment termination as patients treated to remission with antidepressant medications. What remains unclear is whether cognitive therapy truly is enduring or antidepressant medications iatrogenic in terms of prolonging the life of the underlying episode. Depression is an inherently temporal phenomenon and most episodes will remit spontaneously even in the absence of treatment. There is reason to believe that depression is an adaptation that evolved because it keeps organisms focused on (ruminating about) complex social issues until they can be resolved and that medications work not so much by addressing a nonexistent deficit in neurotransmitters in the synapse as by perturbing underlying regulatory mechanisms to the point that they reassert homeostatic control over those systems. If the latter is true then medications may work to suppress symptoms in a manner that leaves the underlying episode unaddressed and patients at elevated risk of relapse whenever they are taken away. Cognitive therapy is predicated on the notion that people become depressed because they misinterpret life events in a negative fashion and that helping them examine the accuracy of their beliefs will relieve their distress. Such an approach would not work if patients were not capable of thinking clearly (if their "brains were broken") and it is likely that cognitive therapy works by making rumination more efficient so as to facilitate the resolution of the complex social issue(s) that brought the episode about. Public Significance StatementThere is reason to think that depression may be an adaptation (like pain or anxiety) that evolved in our ancestral past to help resolve complex social problems. If true then interventions like cognitive therapy that facilitate the functions that depression evolved to serve may be preferred over antidepressant medications that merely anesthetize the distress.

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Section: Depression As An Evolved Adaptationmentioning

confidence: 99%

Is cognitive therapy enduring or antidepressant medications iatrogenic? Depression as an evolved adaptation.

Hollon¹

2020

American Psychologist

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“…Studies in rodent neurons have also shown that 5‐HT promotes the upregulation of Sirt 1 SIRT1; a NAD + ‐dependent deacetylase induces mitochondrial biogenesis involving PGC‐1α that regulates transcription of mitochondrial transcription factor A (TFAM), a gene required for mitochondrial biogenesis, the result of which is reflected in the altered levels of mtDNA. The study also showed that lower levels of 5‐HT affect the biogenesis of mitochondria by master regulators SIRT1 and PGC‐1α, respiratory capacity and OXPHOS efficiency and obviously decreases efficiency of ATP synthesis (Fanibunda et al, 2019). Such a chain of dysfunctional reactions can increase the susceptibility of migraine.…”

Section: Genetic Perspectives and Evidence Of Dysfunction From The Mi...mentioning

confidence: 99%

Current perspectives on mitochondrial dysfunction in migraine

Bohra¹,

Achar

Chidambaram

et al. 2022

Eur J of Neuroscience

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Mitochondria are an autonomous organelle that plays a crucial role in the metabolic aspects of a cell. Cortical spreading depression (CSD) and fluctuations in the cerebral blood flow have for long been mechanisms underlying migraine. It is a neurovascular disorder with a unilateral manifestation of disturbing, throbbing and pulsating head pain. Migraine affects 2.6% and 21.7% of the general population and is the major cause of partial disability in the age group 15–49. Higher mutation rates, imbalance in concentration of physiologically relevant molecules and oxidative stress biomarkers have been the main themes of discussion in determining the role of mitochondrial disability in migraine. The correlation of migraine with other disorders like hemiplegic migraine; mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes [MELAS]; tension‐type headache (TTH); cyclic vomiting syndrome (CVS), ischaemic stroke; and hypertension has helped in the assessment of the physiological and morphogenetic basis of migraine. Here, we have reviewed the different nuances of mitochondrial dysfunction and migraine. The different mtDNA polymorphisms that can affect the generation and transmission of nerve impulse has been highlighted and supported with research findings. In addition to this, the genetic basis of migraine pathogenesis as a consequence of mutations in nuclear DNA that can, in turn, affect the synthesis of defective mitochondrial proteins is discussed along with a brief overview of epigenetic profile. This review gives an overview of the pathophysiology of migraine and explores mitochondrial dysfunction as a potential underlying mechanism. Also, therapeutic supplements for managing migraine have been discussed at different junctures in this paper.

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“…Furthermore, impaired mitochondrial biogenesis is evident in patients with AD and PD (Sheng et al, 2012; Thomas et al, 2012). Using a combination of selective antagonists and KO animals, Vaidya and co‐workers demonstrated that activation of 5‐HT 2A receptors promotes mitochondrial biogenesis and improves mitochondrial function, potentially improving the ability of neurons to buffer stress (Fanibunda et al, 2019). In cortical cultures, stimulation of 5‐HT 2A receptors with DOI protected neurons against both kainate‐ and H 2 O 2 ‐induced cell death (Fanibunda et al, 2019).…”

Section: Role Of 5‐ht2a Receptors In Mitochondrial Functionmentioning

confidence: 99%

“…Using a combination of selective antagonists and KO animals, Vaidya and co‐workers demonstrated that activation of 5‐HT 2A receptors promotes mitochondrial biogenesis and improves mitochondrial function, potentially improving the ability of neurons to buffer stress (Fanibunda et al, 2019). In cortical cultures, stimulation of 5‐HT 2A receptors with DOI protected neurons against both kainate‐ and H 2 O 2 ‐induced cell death (Fanibunda et al, 2019). Moreover, mitochondrial biogenesis was promoted by both the hallucinogenic 5‐HT 2A agonist DOI and the non‐hallucinogenic agonist lisuride (Fanibunda et al, 2019).…”

Section: Role Of 5‐ht2a Receptors In Mitochondrial Functionmentioning

confidence: 99%

“…In cortical cultures, stimulation of 5‐HT 2A receptors with DOI protected neurons against both kainate‐ and H 2 O 2 ‐induced cell death (Fanibunda et al, 2019). Moreover, mitochondrial biogenesis was promoted by both the hallucinogenic 5‐HT 2A agonist DOI and the non‐hallucinogenic agonist lisuride (Fanibunda et al, 2019). This effect does not seem to be limited to neurons, as other cell types expressing 5‐HT 2A receptors will undergo mitochondrial biogenesis and/or increase mitochondria oxidative capacity following stimulation with 5‐HT 2A agonists (Damiano et al, 2021; Harmon et al, 2016; Rasbach et al, 2010).…”

Section: Role Of 5‐ht2a Receptors In Mitochondrial Functionmentioning

confidence: 99%

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