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Introduction: The contribution of Cannabinoid type 1 receptor (CB1) in mitochondrial energy transduction mechanisms and mitochondrial activities awaits deeper investigations. Our study aims to assess the impact of CB1 absence on the mitochondrial compartment in the liver, focusing on both functional aspects and remodeling processes., Methods: We used CB1 -/- and CB1 +/+ male mice. Cytochrome C Oxidase activity was determined polarographically. The expression and the activities of separated mitochondrial complexes and supercomplexes were performed by using Blue-Native Page, Western blotting and histochemical staining for in-gel activity. Key players of Mitochondrial Quality Control processes were measured using RT-qPCR and Western blotting. Liver fine sub-cellular ultrastructural features were analyzed by TEM analysis., Results and Discussion: In the absence of CB1, several changes in the liver occur, including increased oxidative capacity, reduced complex I activity, enhanced complex IV activity, general upregulation of respiratory supercomplexes, as well as higher levels of oxidative stress. The mitochondria and cellular metabolism may be affected by these changes, increasing the risk of ROS-related damage. CB1 -/- mice show upregulation of mitochondrial fusion, fission and biogenesis processes which suggests a dynamic response to the absence of CB1. Furthermore, oxidative stress disturbs mitochondrial proteostasis, initiating the mitochondrial unfolded protein response (UPR mt ). We noted heightened levels of pivotal enzymes responsible for maintaining mitochondrial integrity, along with heightened expression of molecular chaperones and transcription factors associated with cellular stress reactions. Additionally, our discoveries demonstrate a synchronized reaction to cellular stress, involving both UPR mt and UPR ER pathways., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Senese, Petito, Silvestri, Ventriglia, Mosca, Potenza, Russo, Falvo, Manfrevola, Cobellis, Chioccarelli, Porreca, Mele, Chianese, de Lange, Ricci, Cioffi and Lanni.)

In humans and mice, Nkx2-1 and Pax8 are crucial morphogenic transcription factors defining the early development of the thyroid and specific extrathyroidal tissues. By using 3-month-old single or double heterozygotes for Nkx2-1- and Pax8-null mutations (DHTP) mice, we studied brain abnormalities under different human-like dysthyroidisms, focusing on putative alterations of specific neurotransmitter systems, expression of markers of pre- and post-synaptic function and, given the physio-pathological role mitochondria have in controlling the bioenergetic status of neurons, of mitochondrial dynamics and oxidative balance. Compared to Wt controls, DHTP mice, bearing both systemic and brain hypothyroidism, showed altered expression of synaptic markers, generic and cholinergic (corroborated by immunohistochemistry in caudate, putamen, hippocampus, and basal forebrain) and glutamatergic ones, and reduced expression of key proteins of synaptic plasticity potency and several isoforms of glutamate receptors. The brain of DHTP mice was characterized by lower levels of H 2 O 2 and imbalanced mitochondrial dynamics. Nkx2-1 + / - mice showed dopaminergic neuron-specific alterations, morphologically, more evident in the substantia nigra of DHTP mice. Nkx2-1 + / - mice also showed enhanced mitochondrial biogenesis and oxidative capacity likely as a global response of the brain to Nkx2-1 haploinsufficiency and/or to their elevated T3 circulating levels. Reduced transcription of both tyrosine hydroxylase and dopamine transporter was observed in Pax8 + / - euthyroid mice, suggesting a dopaminergic dysfunction, albeit likely at an early stage, but consistent with the deregulated glucose homeostasis observed in such animals. Overall, new information was obtained on the impact of haploinsufficiency of Pax8 and NKx2-1 on several brain neuroanatomical, molecular, and neurochemical aspects, thus opening the way for future targeting brain dysfunctions in the management of both overt and subclinical thyroid dysfunctions., (© 2024. The Author(s).)

Maintaining a well-functioning mitochondrial network through the mitochondria quality control (MQC) mechanisms, including biogenesis, dynamics and mitophagy, is crucial for overall health. Mitochondrial dysfunction caused by oxidative stress and further exacerbated by impaired quality control can trigger inflammation through the release of the damage-associated molecular patterns (mtDAMPs). mtDAMPs act by stimulating the cyclic GMP-AMP synthase (cGAS) stimulator of interferon genes (STING) pathway. Recently, aberrant signalling of the cGAS-STING axis has been recognised to be closely associated with several sterile inflammatory diseases (e.g. non-alcoholic fatty liver disease, obesity). This may fit the pathophysiology of hypothyroidism, an endocrine disorder characterised by the reduction of thyroid hormone production associated with impaired metabolic fluxes, oxidative balance and inflammatory status. Both 3,5,3'-triiodo-L-tyronine (T3) and its derivative 3,5-diiodo-L-thyronine (3,5-T2), are known to mitigate processes targeting mitochondria, albeit the underlying mechanisms are not yet fully understood. Therefore, we used a chemically induced hypothyroidism rat model to investigate the effect of 3,5-T2 or T3 administration on inflammation-related factors (inflammatory cytokines, hepatic cGAS-STING pathway), oxidative stress, antioxidant defence enzymes, mitochondrial DNA (mtDNA) damage, release and repair, and the MQC system in the liver. Hypothyroid rats showed: i) increased oxidative stress, ii) accumulation of mtDNA damage, iii) high levels of circulating cytokines, iv) hepatic activation of cGAS-STING pathways and v) impairment of MQC mechanisms and autophagy. Both iodothyronines restored oxidative balance by enhancing antioxidant defence, preventing mtDNA damage through the activation of mtDNA repair mechanisms (OGG1, APE1, and POLγ) and promoting autophagy progression. Concerning MQC, both iodothyronines stimulated mitophagy and dynamics, with 3,5-T2 activating fusion and T3 modulating both fusion and fission processes. Moreover, only T3 enhanced mitochondrial biogenesis. Notably, 3,5-T2, but not T3, reversed the hypothyroidism-induced activation of the cGAS-STING inflammatory cascade. In addition, it is noteworthy that 3,5-T2 seems more effective than T3 in reducing circulating pro-inflammatory cytokines IL-6 and IL-1B and in stimulating the release of IL-10, a known anti-inflammatory cytokine. These findings reveal novel molecular mechanisms of hepatic signalling pathways involved in hypothyroidism, which could be targeted by natural iodothyronines, particularly 3,5-T2, paving the way for the development of new treatment strategies for inflammatory diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Giacco, Petito, Silvestri, Scopigno, Vigliotti, Mercurio, de Lange, Lombardi, Moreno, Goglia, Lanni, Senese and Cioffi.)

This study aims to explore the complex role of cannabinoid type 1 receptor (CB1) signaling in the gastrocnemius muscle, assessing physiological processes in both CB1 +/+ and CB1 -/- mice. The primary focus is to enhance our understanding of how CB1 contributes to mitochondrial homeostasis. At the tissue level, CB1 -/- mice exhibit a substantial miRNA-related alteration in muscle fiber composition, characterized by an enrichment of oxidative fibers. CB1 absence induces a significant increase in the oxidative capacity of muscle, supported by elevated in-gel activity of Complex I and Complex IV of the mitochondrial respiratory chain. The increased oxidative capacity is associated with elevated oxidative stress and impaired antioxidant defense systems. Analysis of mitochondrial biogenesis markers indicates an enhanced capacity for new mitochondria production in CB1 -/- mice, possibly adapting to altered muscle fiber composition. Changes in mitochondrial dynamics, mitophagy response, and unfolded protein response (UPR) pathways reveal a dynamic interplay in response to CB1 absence. The interconnected mitochondrial network, influenced by increased fusion and mitochondrial UPR components, underlines the dual role of CB1 in regulating both protein quality control and the generation of new mitochondria. These findings deepen our comprehension of the CB1 impact on muscle physiology, oxidative stress, and MQC processes, highlighting cellular adaptability to CB1 -/- . This study paves the way for further exploration of intricate signaling cascades and cross-talk between cellular compartments in the context of CB1 and mitochondrial homeostasis.

Background: The main contribution of this article is establishing a set of behaviors and successful actions experimenting the Ipacs' (Institutional & Public Coaching Services) methodology on implementation of the National Recovery Plan (NRP), approved in Italy in 2021 to overcome the socio-economic impact of the pandemic. This research is aimed at pointing out emotional intelligence (EI) behaviors related to the activities of the NRP with respect to the National Health System (NHS)., Participants and Procedure: Fifty-six professionals were provided with an integrated pathway with coaching, participative art and mentoring from January to June 2022. A "core set" of 5 soft skills - communication, result orientation, teamwork, networking, and emotional intelligence - was measured before and after an integrated coaching pathway. Each soft skill related to the following three systemic objectives through pre-defined, related activities: 1) defining and introducing new roles in the health community houses; 2) implementing a new systemic communication in oncology; 3) facilitating the management of chronicity through a new IT platform. We observed that the Giunti test (Org-EIQ) and Ipacs' test enlighten the same emotional intelligence indicators of behaviors considered by the investigated coaching integrated pathway., Results: Forty-eight percent of them increased in all 5 core skills. Results were measured at least in one of the two tests. These results were possible thanks to the changes in abilities of self- introspection, in communicating and sharing common goals, to achieve high standard results in conditions of uncertainty, to understand non-verbal feedback and give feedback., Conclusions: Emotional intelligence acted as a meta skill to pursue a "new model of man" with a new self-schema, self-image and set of behaviors., Competing Interests: The authors declare no conflict of interest., (Copyright © Institute of Psychology, University of Gdansk.)