Energy metabolic pathways in neuronal development and function

Rumpf, Sebastian; Sanal, Neeraja; Marzano, Marco

doi:10.1093/oons/kvad004

Cited by 3 publications

(1 citation statement)

References 68 publications

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“…A growing body of data has implicated the glycolytic pathway in supporting multiple physiological and pathological processes, including immune cell development and function, neural and organ development, angiogenesis, tumorigenesis, and chemoresistance [23][24][25][26][27][28][29]. As a glycolytic regulator, PFKFB3 performs a critical function in these processes, and accordingly, the development of a PFKFB3 homozygous knockout model is vital for the accurate assessment of its role.…”

Section: Introductionmentioning

confidence: 99%

Genomic Deletion of PFKFB3 Decreases In Vivo Tumorigenesis

Imbert-Fernandez,

Chang,

Lanceta

et al. 2024

Cancers

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Rapidly proliferative processes in mammalian tissues including tumorigenesis and embryogenesis rely on the glycolytic pathway for energy and biosynthetic precursors. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) plays an important regulatory role in glycolysis by activating the key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1). We have previously determined that decreased PFKFB3 expression reduced glycolysis and growth in transformed cells in vitro and suppressed xenograft growth in vivo. In earlier studies, we created a constitutive knockout mouse to interrogate the function of PFKFB3 in vivo but failed to generate homozygous offspring due to the requirement for PFKFB3 for embryogenesis. We have now developed a novel transgenic mouse model that exhibits inducible homozygous pan-tissue Pfkfb3 gene deletion (Pfkfb3fl/fl). We have induced Pfkfb3 genomic deletion in these mice and found that it effectively decreased PFKFB3 expression and activity. To evaluate the functional consequences of Pfkfb3 deletion in vivo, we crossed Cre-bearing Pfkfb3fl/fl mice with oncogene-driven tumor models and found that Pfkfb3 deletion markedly decreased their glucose uptake and growth. In summary, our studies reveal a critical regulatory function for PFKFB3 in glycolysis and tumorigenesis in vivo and characterize an effective and powerful model for further investigation of its role in multiple biological processes.

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Section: Introductionmentioning

confidence: 99%

Genomic Deletion of PFKFB3 Decreases In Vivo Tumorigenesis

Imbert-Fernandez,

Chang,

Lanceta

et al. 2024

Cancers

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High OXPHOS efficiency in RA-FUdr-differentiated SH-SY5Y cells: involvement of cAMP signalling and respiratory supercomplexes

Matrella,

Valletti,

Gigante

et al. 2024

Sci Rep

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Neurons are highly dependent on mitochondria to meet their bioenergetic needs and understanding the metabolic changes during the differentiation process is crucial in the neurodegeneration context. Several in vitro approaches have been developed to study neuronal differentiation and bioenergetic changes. The human SH-SY5Y cell line is a widely used cellular model and several differentiation protocols have been developed to induce a neuron-like phenotype including retinoic acid (RA) treatment. In this work we obtained a homogeneous functional population of neuron-like cells by a two-step differentiation protocol in which SH-SY5Y cells were treated with RA plus the mitotic inhibitor 2-deoxy-5-fluorouridine (FUdr). RA-FUdr treatment induced a neuronal phenotype characterized by increased expression of neuronal markers and electrical properties specific to excitable cells. In addition, the RA-FUdr differentiated cells showed an enrichment of long chain and unsaturated fatty acids (FA) in the acyl chain composition of cardiolipin (CL) and the bioenergetic analysis evidences a high coupled and maximal respiration associated with high mitochondrial ATP levels. Our results suggest that the observed high oxidative phosphorylation (OXPHOS) capacity may be related to the activation of the cyclic adenosine monophosphate (cAMP) pathway and the assembly of respiratory supercomplexes (SCs), highlighting the change in mitochondrial phenotype during neuronal differentiation.

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The Antinociceptive Role of Nrf2 in Neuropathic Pain: From Mechanisms to Clinical Perspectives

Petrikonis,

Bernatoniene,

Kopustinskiene

et al. 2024

Pharmaceutics

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Neuropathic pain, a chronic condition resulting from nerve injury or dysfunction, presents significant therapeutic challenges and is closely associated with oxidative stress and inflammation, both of which can lead to mitochondrial dysfunction. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a critical cellular defense mechanism against oxidative stress, has emerged as a promising target for neuropathic pain management. Nrf2 modulators enhance the expression of antioxidant and cytoprotective genes, thereby reducing oxidative damage, inflammation, and mitochondrial impairment. This review explores the antinociceptive effects of Nrf2, highlighting how pharmacological agents and natural compounds may be used as potential therapeutic strategies against neuropathic pain. Although preclinical studies demonstrate significant pain reduction and improved nerve function through Nrf2 activation, several clinical challenges need to be addressed. However, emerging clinical evidence suggests potential benefits of Nrf2 modulators in several conditions, such as diabetic neuropathy and multiple sclerosis. Future research should focus on further elucidating the molecular role of Nrf2 in neuropathic pain to optimize its modulation efficacy and maximize clinical utility.

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Energy metabolic pathways in neuronal development and function

Cited by 3 publications

References 68 publications

Genomic Deletion of PFKFB3 Decreases In Vivo Tumorigenesis

Genomic Deletion of PFKFB3 Decreases In Vivo Tumorigenesis

High OXPHOS efficiency in RA-FUdr-differentiated SH-SY5Y cells: involvement of cAMP signalling and respiratory supercomplexes

The Antinociceptive Role of Nrf2 in Neuropathic Pain: From Mechanisms to Clinical Perspectives

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