Serotonin Regulates Mitochondrial Biogenesis and Function in Rodent Cortical Neurons Via the 5-HT Receptor and SIRT1-PGC-1α Axis

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2019 May 11

PMID 31072928

Citations 67

Authors

Sashaina E Fanibunda

Sukrita Deb

Babukrishna Maniyadath

Praachi Tiwari

Utkarsha Ghai

Samir Gupta

Dwight Figueiredo

Noelia Weisstaub

Jay A Gingrich

Ashok D B Vaidya

Ullas Kolthur-Seetharam

Vidita A Vaidya

Affiliations

Soon will be listed here.

Abstract

Mitochondria in neurons, in addition to their primary role in bioenergetics, also contribute to specialized functions, including regulation of synaptic transmission, Ca homeostasis, neuronal excitability, and stress adaptation. However, the factors that influence mitochondrial biogenesis and function in neurons remain poorly elucidated. Here, we identify an important role for serotonin (5-HT) as a regulator of mitochondrial biogenesis and function in rodent cortical neurons, via a 5-HT receptor-mediated recruitment of the SIRT1-PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. We found that 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial components. This resulted in higher mitochondrial respiratory capacity, oxidative phosphorylation (OXPHOS) efficiency, and a consequential increase in cellular ATP levels. Mechanistically, the effects of 5-HT were mediated via the 5-HT receptor and master modulators of mitochondrial biogenesis, SIRT1 and PGC-1α. SIRT1 was required to mediate the effects of 5-HT on mitochondrial biogenesis and function in cortical neurons. In vivo studies revealed that 5-HT receptor stimulation increased cortical mtDNA and ATP levels in a SIRT1-dependent manner. Direct infusion of 5-HT into the neocortex and chemogenetic activation of 5-HT neurons also resulted in enhanced mitochondrial biogenesis and function in vivo. In cortical neurons, 5-HT enhanced expression of antioxidant enzymes, decreased cellular reactive oxygen species, and exhibited neuroprotection against excitotoxic and oxidative stress, an effect that required SIRT1. These findings identify 5-HT as an upstream regulator of mitochondrial biogenesis and function in cortical neurons and implicate the mitochondrial effects of 5-HT in its neuroprotective action.

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References

Nebigil C, Etienne N, Messaddeq N, Maroteaux L . Serotonin is a novel survival factor of cardiomyocytes: mitochondria as a target of 5-HT2B receptor signaling. FASEB J. 2003; 17(10):1373-5. DOI: 10.1096/fj.02-1122fje. View

Kondoh M, Shiga T, Okado N . Regulation of dendrite formation of Purkinje cells by serotonin through serotonin1A and serotonin2A receptors in culture. Neurosci Res. 2003; 48(1):101-9. DOI: 10.1016/j.neures.2003.10.001. View

Brunet A, Sweeney L, Sturgill J, Chua K, Greer P, Lin Y . Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004; 303(5666):2011-5. DOI: 10.1126/science.1094637. View

St-Pierre J, Drori S, Uldry M, Silvaggi J, Rhee J, Jager S . Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006; 127(2):397-408. DOI: 10.1016/j.cell.2006.09.024. View

Azmitia E . Serotonin and brain: evolution, neuroplasticity, and homeostasis. Int Rev Neurobiol. 2006; 77:31-56. DOI: 10.1016/S0074-7742(06)77002-7. View

Gonzalez-Maeso J, Weisstaub N, Zhou M, Chan P, Ivic L, Ang R . Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior. Neuron. 2007; 53(3):439-52. DOI: 10.1016/j.neuron.2007.01.008. View

Chen S, Owens G, Crossin K, Edelman D . Serotonin stimulates mitochondrial transport in hippocampal neurons. Mol Cell Neurosci. 2007; 36(4):472-83. DOI: 10.1016/j.mcn.2007.08.004. View

Riccio O, Potter G, Walzer C, Vallet P, Szabo G, Vutskits L . Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6. Mol Psychiatry. 2008; 14(3):280-90. DOI: 10.1038/mp.2008.89. View

Chen S, Owens G, Edelman D . Dopamine inhibits mitochondrial motility in hippocampal neurons. PLoS One. 2008; 3(7):e2804. PMC: 2467486. DOI: 10.1371/journal.pone.0002804. View

10.

Millan M, Marin P, Bockaert J, Mannoury la Cour C . Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions. Trends Pharmacol Sci. 2008; 29(9):454-64. DOI: 10.1016/j.tips.2008.06.007. View

11.

Nicholls D . Oxidative stress and energy crises in neuronal dysfunction. Ann N Y Acad Sci. 2008; 1147:53-60. DOI: 10.1196/annals.1427.002. View

12.

Mattson M, Gleichmann M, Cheng A . Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008; 60(5):748-66. PMC: 2692277. DOI: 10.1016/j.neuron.2008.10.010. View

13.

Wareski P, Vaarmann A, Choubey V, Safiulina D, Liiv J, Kuum M . PGC-1{alpha} and PGC-1{beta} regulate mitochondrial density in neurons. J Biol Chem. 2009; 284(32):21379-85. PMC: 2755862. DOI: 10.1074/jbc.M109.018911. View

14.

Hock M, Kralli A . Transcriptional control of mitochondrial biogenesis and function. Annu Rev Physiol. 2009; 71:177-203. DOI: 10.1146/annurev.physiol.010908.163119. View

15.

Onyango I, Lu J, Rodova M, Lezi E, Crafter A, Swerdlow R . Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim Biophys Acta. 2009; 1802(1):228-34. DOI: 10.1016/j.bbadis.2009.07.014. View

16.

Philp A, Chen A, Lan D, Meyer G, Murphy A, Knapp A . Sirtuin 1 (SIRT1) deacetylase activity is not required for mitochondrial biogenesis or peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) deacetylation following endurance exercise. J Biol Chem. 2011; 286(35):30561-30570. PMC: 3162416. DOI: 10.1074/jbc.M111.261685. View

17.

Libert S, Pointer K, Bell E, Das A, Cohen D, Asara J . SIRT1 activates MAO-A in the brain to mediate anxiety and exploratory drive. Cell. 2011; 147(7):1459-72. PMC: 3443638. DOI: 10.1016/j.cell.2011.10.054. View

18.

Manji H, Kato T, Di Prospero N, Ness S, Beal M, Krams M . Impaired mitochondrial function in psychiatric disorders. Nat Rev Neurosci. 2012; 13(5):293-307. DOI: 10.1038/nrn3229. View

19.

Price N, Gomes A, Ling A, Duarte F, Martin-Montalvo A, North B . SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012; 15(5):675-90. PMC: 3545644. DOI: 10.1016/j.cmet.2012.04.003. View

20.

Scarpulla R, Vega R, Kelly D . Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol Metab. 2012; 23(9):459-66. PMC: 3580164. DOI: 10.1016/j.tem.2012.06.006. View