Biology subjects

Muccioli, G. G.

Publications and source records attributed to Muccioli, G. G..

3 recordsLinked to original sources

bioRxiv2026

Alzheimer's disease-associated Presenilin 2 N141I mutation impairs neuronal lipid homeostasis and mitochondrial dynamics through selective downregulation of the Golgi exchange factor Gbf1

Presenilin 2 (PS2) mutations cause familial Alzheimers disease, yet their effects beyond amyloid processing remain poorly understood. Here, we investigated how PS2 deletion and the N141I mutation affect neuronal lipid homeostasis and mitochondrial dynamics in mouse primary neurons. Both PS2 deletion and N141I mutation reduced neuronal lipid content. However, exogenous lipid supplementation rescued this deficit only in N141I-expressing neurons, indicating a partial loss-of-function effect. N141I neurons also displayed reduced OPA1, a mitochondrial fusion regulator, restored by lipid supplementation. RNA-sequencing identified Gbf1, a Golgi-specific guanine nucleotide exchange factor, as selectively downregulated in N141I but not knockout tissue, which was confirmed at the protein level in mouse brain and primary neurons. Gbf1 knockdown in mouse embryonic fibroblasts (MEFs) recapitulated the N141I lipid profile. Together, these findings reveal a PS2-GBF1-lipid-mitochondria axis disrupted specifically by the N141I mutation, suggesting an amyloid-independent pathway contributing to neurodegeneration and identifying potential therapeutic targets for familial Alzheimers disease.

neuroscience↗

bioRxiv2020

Identification of an endocannabinoid gut-brain vagal mechanism controlling food reward and energy homeostasis

The regulation of food intake, a sine qua non requirement for survival, thoroughly shapes feeding and energy balance by integrating both homeostatic and hedonic values of food. Unfortunately, the widespread access to palatable food has led to the development of feeding habits that are independent from metabolic needs. Among these, binge eating (BE) is characterized by uncontrolled voracious eating. While reward deficit seems to be a major contributor of BE, the physiological and molecular underpinnings of BE establishment remain elusive. Here, we combined a physiologically relevant BE mouse model with multiscale in vivo approaches to explore the functional connection between the gut-brain axis and the reward and homeostatic brain structures. Our results show that BE elicits compensatory adaptations requiring the gut-to-brain axis which, through the vagus nerve, relies on the permissive actions of peripheral endocannabinoids (eCBs) signaling. Selective inhibition of peripheral CB1 receptors resulted in a vagus-dependent increased hypothalamic activity, modified metabolic efficiency, and dampened activity of mesolimbic dopamine circuit, altogether leading to the suppression of palatable eating. We provide compelling evidence for a yet unappreciated physiological integrative mechanism by which variations of peripheral eCBs control the activity of the vagus nerve, thereby in turn gating the additive responses of both homeostatic and hedonic brain circuits which govern homeostatic and reward-driven feeding. In conclusion, we reveal that vagus-mediated eCBs/CB1R functions represent an interesting and innovative target to modulate energy balance and counteract food-reward disorders.

neuroscience↗

bioRxiv2019

CANCER-ASSOCIATED FIBROBLASTS PROMOTE PROSTATE CANCER MALIGNANCY VIA METABOLIC REWIRING AND MITOCHONDRIAL TRANSFER

Cancer-associated fibroblasts (CAFs) are the major cellular stromal component of many solid tumors. In prostate cancer (PCa), CAFs establish a metabolic symbiosis with PCa cells, contributing to cancer aggressiveness through lactate shuttle. In this study, we report that lactate uptake alters the NAD+/NADH ratio in the cancer cells, which culminates with SIRT1-dependent PGC-1 activation and subsequent enhancement of mitochondrial mass and activity. The high exploitation of mitochondria results in tricarboxylic acid cycle deregulation, accumulation of oncometabolites and in the altered expression of mitochondrial complexes, responsible for superoxide generation. Additionally, cancer cells hijack CAF-derived functional mitochondria through the formation of cellular bridges, a phenomenon that we observed in both in vitro and in vivo PCa models. Our work reveals a crucial function of tumor mitochondria as the energy sensors and transducers of CAF-dependent metabolic reprogramming and underscores the reliance of PCa cells on CAF catabolic activity and mitochondria trading.

cancer biology↗