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

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. 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-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. 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.Fil: Fanibunda, S. E.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; España. Kasturba Health Society; IndiaFil: Deb, Sukrita. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Maniyadath, Babukrishna. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Tiwari, Praachi. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Ghai, Utkarsha. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Gupta, Samir. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Figueiredo, Dwight. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Weisstaub, Noelia V.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Gingrich, Jay A.. Columbia University; Estados UnidosFil: Vaidya, Ashok D.B.. Kasturba Health Society; IndiaFil: Kolthur Seetharam, Ullas. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; EspañaFil: Vaidya, Vidita A.. International Centre Of Theoretical Science. Tata Institute Of Fundamental Research; Españ

Specialization of the general transcriptional machinery in male germ cells.

International audienceIn adult animals, spermatogenesis involves a continuous differentiation of the spermatogonial stem and progenitor cell population into mature sperm. A unique aspect of this developmental process is the germ cell-specific expression and function of paralogues of components of the general transcription machinery, notably subunits of TFIID. Genetic and biochemical studies show that these paralogues play critical, but mechanistically distinct roles in Drosophila and mouse spermatogenesis

Dendritic Fibrous Nanosilica (DFNS) for RNA Extraction from Cells

Efficient RNA extraction is critical for all downstream molecular applications and techniques. Despite the availability of several commercial kits, there is an enormous scope to develop novel materials that have high binding and elution capacities. Here we show that RNA from the cells can be extracted by dendritic fibrous nanosilica (DFNS) with higher efficiency than commercially available silica. This could be because of the unique fibrous morphology, high accessible surface area, and nano-size particles of DFNS. We studied various fundamental aspects, including the role of particle size, morphology, surface area, and charge on silica surface on RNA extraction efficiency. Infrared spectroscopy (FTIR) studies revealed the interaction of functional groups of the RNA with the silica surface, causing selective binding. Due to the sustainable synthesis protocol of DFNS, the simplicity of various buffers and washing solutions used, this RNA extraction kits can be assembled in any lab. In addition to the fundamental aspects of DFNS-RNA interactions, this study has the potential to initiate the development of indigenous DFNS based kits for RNA extraction

Control of AIF-mediated cell death by the functional interplay of SIRT1 and PARP-1 in response to DNA damage

Cell survival after genotoxic stress is determined by a counterbalance of pro- and anti-death factors. Sirtuins (SIRTs) are deacetylases that promote cell survival whereas poly(ADP-ribose) polymerases (PARPs) can act both as survival and death inducing factor and the two protein families are strictly dependent on NAD(+) for their activities. Here we report that SIRT1 modulates PARP-1 activity upon DNA damage. Activation of SIRT1 by resveratrol leads to reduced PARP-1 activity and there is a drastic increase in PAR synthesis in sirt1-null cells. The unbalanced regulation of PARP-1 in the absence of SIRT1 results in AIF (apoptosis inducing factor)-mediated cell death. Our findings establish a functional link between the two NAD+-dependent enzyme systems and provide a physiological interpretation for the mechanism of death in cells lacking SIRT1

dSir2 in the Adult Fat Body, but Not in Muscles, Regulates Life Span in a Diet-Dependent Manner

Sir2, an evolutionarily conserved NAD+-dependent deacetylase, has been implicated as a key factor in mediating organismal life span. However, recent contradictory findings have brought into question the role of Sir2 and its orthologs in regulating organismal longevity. In this study, we report that Drosophila Sir2 (dSir2) in the adult fat body regulates longevity in a diet-dependent manner. We used inducible Gal4 drivers to knock down and overexpress dSir2 in a tissue-specific manner. A diet-dependent life span phenotype of dSir2 perturbations (both knockdown and overexpression) in the fat body, but not muscles, negates the effects of background genetic mutations. In addition to providing clarity to the field, our study contrasts the ability of dSir2 in two metabolic tissues to affect longevity. We also show that dSir2 knockdown abrogates fat-body dFOXO-dependent life span extension. This report highlights the importance of the interplay between genetic factors and dietary inputs in determining organismal life spans

The histone deacetylase SIRT1 controls male fertility in mice through regulation of hypothalamic-pituitary gonadotropin signaling

Sirtuins (SIRTs) are class-III NAD-dependent histone deacetylases (HDACs) that regulate various physiological processes. Inactivation of SIRT1 in the mouse leads to male sterility, but the molecular mechanisms responsible for this phenotype have not been determined. Here we show that fetal testis development appears normal in Sirt1(-/-) mice. In contrast, the first round of spermatogenesis arrests before the completion of meiosis with abundant apoptosis of pachytene spermatocytes, abnormal Leydig and Sertoli cell maturation, and strongly reduced intratesticular testosterone levels. We show that this phenotype is the consequence of diminished hypothalamic gonadotropin-releasing hormone expression and strongly reduced luteinizing hormone levels. Rather than having an intrinsic effect on male germ cells per se, our results show that SIRT1 regulates spermatogenesis at postnatal stages by controlling hypothalamus-pituitary gonadotropin (HPG) signaling. In addition to its well studied role in control of metabolism and energy homeostasis, our results thus reveal a novel and critical function of SIRT1 in controlling HPG signaling. This phenotype is more severe than those previously described using mice bred on different genetic backgrounds, and highlights the fact that SIRT1 function is strongly modified by other genetic loc