Complete neural stem cell (NSC) neuronal differentiation requires a branched chain amino acids-induced persistent metabolic shift towards energy metabolism

Bifari, Francesco; Dolci, Sissi; Bottani, Emanuela; Pino, Annachiara; Chio, Marzia Di; Zorzin, Stefania; Ragni, Maurizio; Zamfir, Raluca Georgiana; Brunetti, Dario; Bardelli, Donatella; Delfino, Pietro; Cattaneo, Maria Grazia; Bordo, Roberta; Tedesco, Laura; Rossi, Fábio; Bossolasco, Patrizia; Corbo, Vincenzo; Fumagalli, Guido Francesco; Nisoli, Enzo; Valerio, Alessandra; Decimo, Ilaria

doi:10.1016/j.phrs.2020.104863

Cited by 31 publications

(32 citation statements)

References 94 publications

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“…We recently tested inductors of oxidative metabolism (developed and patented by Professional Dietetics, IT) composed of TCA cycle intermediates, specific amino acids, and co-factors that helped enhance mitochondrial function in different in vitro and in vivo models. Supplementing wild-type NSC-culture medium with these compounds during the differentiation phase enhanced the metabolic shift towards OXPHOS and mitochondrial function of mouse and human NSCs, improving their full differentiation capacity [ 422 ]. Neurons derived from treated-NSC changed the fission–fusion processing resulting in a mitochondrial elongated phenotype; moreover, the activation of the mTORC1 pathway with subsequent significant increase of ATP production was reported.…”

Section: Future Perspectivesmentioning

confidence: 99%

“…Neurons derived from treated-NSC changed the fission–fusion processing resulting in a mitochondrial elongated phenotype; moreover, the activation of the mTORC1 pathway with subsequent significant increase of ATP production was reported. Also, the antioxidant defense system was also triggered by the increase of the NRF2 gene expression [ 422 ]. We observed similar metabolic and molecular changes in vivo, where they counteracted the pathological mitochondrial dysfunction occurring during the aging process.…”

Section: Future Perspectivesmentioning

confidence: 99%

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Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

et al. 2020

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Primary mitochondrial diseases (PMD) refer to a group of severe, often inherited genetic conditions due to mutations in the mitochondrial genome or in the nuclear genes encoding for proteins involved in oxidative phosphorylation (OXPHOS). The mutations hamper the last step of aerobic metabolism, affecting the primary source of cellular ATP synthesis. Mitochondrial diseases are characterized by extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. The limited information of the natural history, the limitations of currently available preclinical models, coupled with the large variability of phenotypical presentations of PMD patients, have strongly penalized the development of effective therapies. However, new therapeutic strategies have been emerging, often with promising preclinical and clinical results. Here we review the state of the art on experimental treatments for mitochondrial diseases, presenting “one-size-fits-all” approaches and precision medicine strategies. Finally, we propose novel perspective therapeutic plans, either based on preclinical studies or currently used for other genetic or metabolic diseases that could be transferred to PMD.

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Section: Future Perspectivesmentioning

confidence: 99%

Section: Future Perspectivesmentioning

confidence: 99%

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

et al. 2020

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“…The metabolic effects of SFA-EAA and HFD-EAA diets were compared with those owed to two isocaloric, isolipidic, and isonitrogenous diets, identical to the SFA diet or HFD except for casein replacement by the purified amino acid mixture designed on the amino acid profile of casein (SFA-CAA and HFD-CAA diets), in addition to those induced by a chow diet. In particular, drinking supplementation of the EAA mixture was found to prevent oxidative stress in metabolically active cells ( 14 – 16 ), ameliorating muscle and cognitive performance in diverse animal models and humans ( 17 , 18 ). Moreover, a relevant rejuvenation was observed in the gut microbiota of aging mice supplemented with the EAA mixture ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Manipulation of Dietary Amino Acids Prevents and Reverses Obesity in Mice Through Multiple Mechanisms That Modulate Energy Homeostasis

et al. 2020

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Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance because such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, we show that a designer protein-deprived diet enriched in free essential amino acids can 1 ) promote the brown fat thermogenic program and fatty acid oxidation, 2 ) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, 3 ) change the gut microbiota composition, and 4 ) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy life span. These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by in vitro experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

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“…Mitochondrial demise can be observed even before the appearance of pathognomonic histopathological hallmarks of the disease [5]. Neurons are obligatorily dependent on mitochondrial energy production, which sustains a myriad of functions, including membrane remodeling, synaptic spine formation, and the generation of transmembrane resting and action potentials [6,7].…”

Section: Introductionmentioning

confidence: 99%

Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration

et al. 2021

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Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aβ). In this review, we present current evidence obtained from patients with PITRM1 mutations, as well as the different cellular and animal models of PITRM1 deficiency, which points toward PITRM1 as a possible driving factor of several neurodegenerative conditions. Finally, we point out the prospect of new diagnostic and therapeutic approaches.

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Complete neural stem cell (NSC) neuronal differentiation requires a branched chain amino acids-induced persistent metabolic shift towards energy metabolism

Cited by 31 publications

References 94 publications

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies

Manipulation of Dietary Amino Acids Prevents and Reverses Obesity in Mice Through Multiple Mechanisms That Modulate Energy Homeostasis

Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration

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