Histone Deacetylase Inhibitors in Cell Pluripotency, Differentiation, and Reprogramming

Histone deacetylase inhibitors (HDACi) are small molecules that have important and pleiotropic effects on cell homeostasis. Under distinct developmental conditions, they can promote either self-renewal or differentiation of embryonic stem cells. In addition, they can promote directed differentiation of embryonic and tissue-specific stem cells along the neuronal, cardiomyocytic, and hepatic lineages. They have been used to facilitate embryo development following somatic cell nuclear transfer and induced pluripotent stem cell derivation by ectopic expression of pluripotency factors. In the latter method, these molecules not only increase effectiveness, but can also render the induction independent of the oncogenes c-Myc and Klf4. Here we review the molecular pathways that are involved in the functions of HDAC inhibitors on stem cell differentiation and reprogramming of somatic cells into pluripotency. Deciphering the mechanisms of HDAC inhibitor actions is very important to enable their exploitation for efficient and simple tissue regeneration therapies

A mitochondrial rheostat drives germline stem cell differentiation in Caenorhabditis elegans

The C. elegans germline recapitulates mammalian stem cell niches, and has proven instrumental in understanding key aspects of stem cell biology. However, the molecular and physiological requirements for germline stem cell homeostasis remain largely elusive. We investigated the role of mitochondrial biogenesis and function in the preservation of germline stem cell identity. Here, we show that general transcription activity in germline mitochondria is highly compartmentalized and parallels mitochondrial maturation. Expression of RPOM-1, the mitochondrial RNA polymerase, increases as germ nuclei progress from the distal to the proximal gonadal arm to form oocytes, and is directly regulated by IFET-1, a translational repressor required for normal P granule formation. Mitochondria transition from globular to tubular morphology and become polarized, as they approach the proximal gonad arm. Notably, we find that a similar transition and temporal mitochondrial RNA polymerase expression profile characterizes differentiation of mammalian stem cells. This shift is accompanied by increased ATP and ROS production. Perturbation of mitochondrial bioenergetics causes gonad syncytium hyperplasia by disrupting the balance between mitosis and differentiation to oocytes, resulting in a marked reduction of fecundity. Consequently, compensatory apoptosis is induced in the germline. Sperm-derived signals promote mitochondrial maturation and germ cell differentiation via the MEK/ERK kinase pathway. Germ cell fate decisions are determined by a crosstalk between Insulin/IGF-1 and TGF-β signaling, mitochondria and protein synthesis. Our findings demonstrate that a shift in mitochondrial bioenergetics guides germline stem cell differentiation, and implicate mitochondrial transcription in germ cell differentiation and germline tumor development.Η γαμετική σειρά του C. elegans προσομοιάζει τους βλαστικούς θύλακες των θηλαστικών και έχει αποδειχτεί ανεκτίμητης αξίας για την κατανόηση βασικών πτυχών της βιολογίας των βλαστικών κυττάρων. Παρόλα αυτά, πολλά από τα μοριακά και φυσιολογικά προαπαιτούμενα για τη διατήρηση της ομοιόστασης των γαμετικών βλαστικών κυττάρων παραμένουν άγνωστα. Ερευνήσαμε το ρόλο της μιτοχονδριακής βιογένεσης και λειτουργίας στην διατήρηση της ταυτότητας των γαμετικών βλαστικών κυττάρων. Η δουλειά μας καταδεικνύει πως η μιτοχονδριακή μεταγραφή στα γαμετικά μιτοχόνδρια είναι διαμερισματοποιημένη και έρχεται παράλληλα με την μιτοχονδριακή ωρίμανση. Η έκφραση της RPOM-1, της μιτοχονδριακής RNA πολυμεράσης, αυξάνεται καθώς οι γαμετικοί πυρήνες μεταβαίνουν από τον άπω στον εγγύς βραχίονα της γονάδας και σχηματίζουν ωοκύτταρα. Η έκφραση της RPOM-1 ρυθμίζεται από τον IFET-1, ένα μεταφραστικό καταστολέα και συστατικό των P granules. Τα μιτοχόνδρια αυτά καθ’ αυτά μεταβαίνουν από μια σφαιρική σε μια επιμήκη μορφολογία και πολώνονται καθώς πλησιάζουν τον εγγύς βραχίονα της γονάδας και η παραγωγή ATP και ROS αυξάνεται. Μια αντίστοιχη μετάβαση και αλλαγή στην έκφραση της μιτοχονδριακής RNA πολυμεράσης χαρακτηρίζει και την διαφοροποίηση των βλαστικών κυττάρων των θηλαστικών. Διατάραξη της διαδικασίας αυτής προκαλεί υπερπλασία στο συγκύτιο της γονάδας λόγω αλλαγής στην ισορροπία μεταξύ μίτωσης και διαφοροποίησης σε ωοκύτταρα και ακολουθείται από μείωση της γονιμότητας. Ως αποτέλεσμα, η απόπτωση ενεργοποιείται για να αντισταθμίσει την υπερπλασία. Σήματα σπερματικής προέλευσης (MSP) προάγουν την μιτοχονδριακή ωρίμανση και διαφοροποίηση των γαμετικών κυττάρων μέσω του MEK/ERK μονοπατιού κινασών. Η μοίρα των γαμετικών κυττάρων καθορίζεται από την αλληλεπίδραση των μοναπατιών Insulin/IGF-1, TGF-β, των ρυθμών πρωτεϊνοσύνθεσης και των μιτοχονδρίων. Τα ευρήματα μας εμπλέκουν αλλαγές στη μιτοχονδριακή ενεργότητα στην διαφοροποίηση των βλαστικών κυττάρων και τη μιτοχονδριακή μεταγραφή στη διαφοροποίηση των γαμετικών κυττάρων και την υπερπλασία

Mitophagy and Neuroinflammation: A Compelling Interplay

Mitochondria are the main sites of energy production and a major source of metabolic stress. Not surprisingly, impairment of mitochondrial homeostasis is strongly associated with the development and progression of a broad spectrum of human pathologies, including neurodegenerative disorders. Mitophagy mediates the selective degradation of damaged organelles, thus promoting cellular viability and tissue integrity. Defective mitophagy triggers cellular senescence and prolonged neuroinflammation, leading eventually to cell death and brain homeostasis collapse. Here, we survey the intricate interplay between mitophagy and neuroinflammation, highlighting that mitophagy can be a focal point for therapeutic interventions to tackle neurodegeneration. © 2023 Bentham Science Publishers

Acyl-CoA-binding protein (ACBP): a phylogenetically conserved appetite stimulator

International audienceRecently, we reported that, in mice, hunger causes the autophagy-dependent release of a protein called "acyl-CoA-binding protein" or "diazepam binding inhibitor" (ACBP/DBI) from cells, resulting in an increase in plasma ACBP concentrations. Administration of extra ACBP is orexigenic and obesogenic, while its neutralization is anorexigenic in mice, suggesting that ACBP is a major stimulator of appetite and lipo-anabolism. Accordingly, obese persons have higher circulating ACBP levels than lean individuals, and anorexia nervosa is associated with subnormal ACBP plasma concentrations. Here, we investigated whether ACBP might play a phylogenetically conserved role in appetite stimulation. We found that extracellular ACBP favors sporulation in Saccharomyces cerevisiae, knowing that sporulation is a strategy for yeast to seek new food sources. Moreover, in the nematode Caenorhabditis elegans, ACBP increased the ingestion of bacteria as well as the frequency pharyngeal pumping. These observations indicate that ACBP has a phylogenetically ancient role as a 'hunger factor' that favors food intake

ER-associated RNA silencing promotes ER quality control.

The endoplasmic reticulum (ER) coordinates mRNA translation and processing of secreted and endomembrane proteins. ER-associated degradation (ERAD) prevents the accumulation of misfolded proteins in the ER, but the physiological regulation of this process remains poorly characterized. Here, in a genetic screen using an ERAD model substrate in Caenorhabditis elegans, we identified an anti-viral RNA interference pathway, referred to as ER-associated RNA silencing (ERAS), which acts together with ERAD to preserve ER homeostasis and function. Induced by ER stress, ERAS is mediated by the Argonaute protein RDE-1/AGO2, is conserved in mammals and promotes ER-associated RNA turnover. ERAS and ERAD are complementary, as simultaneous inactivation of both quality-control pathways leads to increased ER stress, reduced protein quality control and impaired intestinal integrity. Collectively, our findings indicate that ER homeostasis and organismal health are protected by synergistic functions of ERAS and ERAD

ER-associated RNA silencing promotes ER quality control

The endoplasmic reticulum (ER) coordinates mRNA translation and processing of secreted and endomembrane proteins. ER-associated degradation (ERAD) prevents the accumulation of misfolded proteins in the ER, but the physiological regulation of this process remains poorly characterized. Here, in a genetic screen using an ERAD model substrate in Caenorhabditis elegans, we identified an anti-viral RNA interference pathway, referred to as ER-associated RNA silencing (ERAS), which acts together with ERAD to preserve ER homeostasis and function. Induced by ER stress, ERAS is mediated by the Argonaute protein RDE-1/AGO2, is conserved in mammals and promotes ER-associated RNA turnover. ERAS and ERAD are complementary, as simultaneous inactivation of both quality-control pathways leads to increased ER stress, reduced protein quality control and impaired intestinal integrity. Collectively, our findings indicate that ER homeostasis and organismal health are protected by synergistic functions of ERAS and ERAD