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

Sashaina E. Fanibunda, Sukrita Deb, Babukrishna Maniyadat, Samir Gupta, Noelia Weisstaub, Jay A. Gingrich, Ashok D.B. Vaidya, Ullas Kolthur-Seetharam, Vidita A. Vaidya
doi: https://doi.org/10.1101/497982
Sashaina E. Fanibunda
1Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
2Medical Research Centre, Kasturba Health Society, Mumbai, India.
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Sukrita Deb
1Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
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Babukrishna Maniyadat
1Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
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Samir Gupta
1Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
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Noelia Weisstaub
3Department of Physiology, Faculty of Medicine, University of Buenos Aires, Argentina.
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Jay A. Gingrich
4Department of Psychiatry, Columbia University, New York.
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Ashok D.B. Vaidya
2Medical Research Centre, Kasturba Health Society, Mumbai, India.
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Ullas Kolthur-Seetharam
1Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
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  • For correspondence: vvaidya@tifr.res.in ullas@tifr.res.in
Vidita A. Vaidya
1Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, India.
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  • For correspondence: vvaidya@tifr.res.in ullas@tifr.res.in
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Abstract

Mitochondria in neurons in addition to their primary role in bioenergetics also contribute to specialized functions including regulation of synaptic transmission, Ca2+ 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-HT2A receptor-mediated recruitment of the SIRT1-PGC-1α axis, which is relevant to the neuroprotective action of 5-HT. 5-HT increased mitochondrial biogenesis, reflected through enhanced mtDNA levels, mitotracker staining, and expression of mitochondrial genes. This was accompanied by increased cellular ATP levels, basal and maximal respiration, as well as spare respiratory capacity. Mechanistically the effects of 5-HT were mediated via the 5-HT2A 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-HT2A receptor stimulation increased cortical mtDNA and ATP levels, in a SIRT1 dependent manner. In cortical neurons, 5-HT enhanced expression of anti-oxidant 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 a novel 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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Posted December 16, 2018.
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Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1α axis
Sashaina E. Fanibunda, Sukrita Deb, Babukrishna Maniyadat, Samir Gupta, Noelia Weisstaub, Jay A. Gingrich, Ashok D.B. Vaidya, Ullas Kolthur-Seetharam, Vidita A. Vaidya
bioRxiv 497982; doi: https://doi.org/10.1101/497982
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Serotonin regulates mitochondrial biogenesis and function in rodent cortical neurons via the 5-HT2A receptor and SIRT1-PGC-1α axis
Sashaina E. Fanibunda, Sukrita Deb, Babukrishna Maniyadat, Samir Gupta, Noelia Weisstaub, Jay A. Gingrich, Ashok D.B. Vaidya, Ullas Kolthur-Seetharam, Vidita A. Vaidya
bioRxiv 497982; doi: https://doi.org/10.1101/497982

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