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1.
Dev Cell ; 59(16): 2143-2157.e9, 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-38843836

RESUMO

Neuronal activity is an energy-intensive process that is largely sustained by instantaneous fuel utilization and ATP synthesis. However, how neurons couple ATP synthesis rate to fuel availability is largely unknown. Here, we demonstrate that the metabolic sensor enzyme O-linked N-acetyl glucosamine (O-GlcNAc) transferase regulates neuronal activity-driven mitochondrial bioenergetics in hippocampal and cortical neurons. We show that neuronal activity upregulates O-GlcNAcylation in mitochondria. Mitochondrial O-GlcNAcylation is promoted by activity-driven glucose consumption, which allows neurons to compensate for high energy expenditure based on fuel availability. To determine the proteins that are responsible for these adjustments, we mapped the mitochondrial O-GlcNAcome of neurons. Finally, we determine that neurons fail to meet activity-driven metabolic demand when O-GlcNAcylation dynamics are prevented. Our findings suggest that O-GlcNAcylation provides a fuel-dependent feedforward control mechanism in neurons to optimize mitochondrial performance based on neuronal activity. This mechanism thereby couples neuronal metabolism to mitochondrial bioenergetics and plays a key role in sustaining energy homeostasis.


Assuntos
Acetilglucosamina , Metabolismo Energético , Mitocôndrias , N-Acetilglucosaminiltransferases , Neurônios , Neurônios/metabolismo , Animais , Mitocôndrias/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , N-Acetilglucosaminiltransferases/genética , Acetilglucosamina/metabolismo , Camundongos , Hipocampo/metabolismo , Hipocampo/citologia , Glucose/metabolismo , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia
2.
Nat Metab ; 6(9): 1712-1735, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39261628

RESUMO

Glucose, the primary cellular energy source, is metabolized through glycolysis initiated by the rate-limiting enzyme hexokinase (HK). In energy-demanding tissues like the brain, HK1 is the dominant isoform, primarily localized on mitochondria, and is crucial for efficient glycolysis-oxidative phosphorylation coupling and optimal energy generation. This study unveils a unique mechanism regulating HK1 activity, glycolysis and the dynamics of mitochondrial coupling, mediated by the metabolic sensor enzyme O-GlcNAc transferase (OGT). OGT catalyses reversible O-GlcNAcylation, a post-translational modification influenced by glucose flux. Elevated OGT activity induces dynamic O-GlcNAcylation of the regulatory domain of HK1, subsequently promoting the assembly of the glycolytic metabolon on the outer mitochondrial membrane. This modification enhances the mitochondrial association with HK1, orchestrating glycolytic and mitochondrial ATP production. Mutation in HK1's O-GlcNAcylation site reduces ATP generation in multiple cell types, specifically affecting metabolic efficiency in neurons. This study reveals a previously unappreciated pathway that links neuronal metabolism and mitochondrial function through OGT and the formation of the glycolytic metabolon, providing potential strategies for tackling metabolic and neurological disorders.


Assuntos
Glicólise , Hexoquinase , Mitocôndrias , N-Acetilglucosaminiltransferases , Mitocôndrias/metabolismo , Hexoquinase/metabolismo , Humanos , N-Acetilglucosaminiltransferases/metabolismo , N-Acetilglucosaminiltransferases/genética , Animais , Neurônios/metabolismo , Trifosfato de Adenosina/metabolismo , Glucose/metabolismo , Processamento de Proteína Pós-Traducional , Camundongos , Fosforilação Oxidativa
3.
Cell Rep ; 42(1): 111943, 2023 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-36640310

RESUMO

The endoplasmic reticulum (ER) is a tortuous organelle that spans throughout a cell with a continuous membrane containing ion channels, pumps, and transporters. It is unclear if stimuli that gate ER ion channels trigger substantial membrane potential fluctuations and if those fluctuations spread beyond their site of origin. Here, we visualize ER membrane potential dynamics in HEK cells and cultured rat hippocampal neurons by targeting a genetically encoded voltage indicator specifically to the ER membrane. We report the existence of clear cell-type- and stimulus-specific ER membrane potential fluctuations. In neurons, direct stimulation of ER ryanodine receptors generates depolarizations that scale linearly with stimulus strength and reach tens of millivolts. However, ER potentials do not spread beyond the site of receptor activation, exhibiting steep attenuation that is exacerbated by intracellular large conductance K+ channels. Thus, segments of ER can generate large depolarizations that are actively restricted from impacting nearby, contiguous membrane.


Assuntos
Retículo Endoplasmático , Neurônios , Animais , Ratos , Cálcio/metabolismo , Retículo Endoplasmático/metabolismo , Hipocampo/metabolismo , Potenciais da Membrana/fisiologia , Neurônios/metabolismo , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Humanos , Linhagem Celular
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