Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein mal- function and mitochondrial dysfunction contribute to the loss...Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein mal- function and mitochondrial dysfunction contribute to the loss of neuronal architecture; however, less is known about the intracallular signaling pathways that can pro- tect against or delay this pathogenic process. Here, we show that the DYNClll deficiency, a neuron-specific dynein intermediate chain, causes neuronal atrophy in primary hippocampal neurons. With this cellular model, we are able to find that activation of RAS-RAF.MEK signaling protects against neuronal atrophy induced by DYNClll deficiency, which relies on MEK-dependent autophagy in neuron. Moreover, we further reveal that BRAF also protects against neuronal atrophy induced by mitochondrial impairment. These findings demon- strate protective roles of the RAS-RAF-MEK axis against neuronal atrophy, and imply a new therapeutic target for clinical intervention.展开更多
Obesity is a worldwide epidemic and results from excessive energy intake or inefficient energy expenditure.It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention.However,t...Obesity is a worldwide epidemic and results from excessive energy intake or inefficient energy expenditure.It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention.However,the mechanisms controlling the efficacy of norepinephrine-induced thermogenesis in brown adipocytes remain elusive.Here we demonstrate that norepinephrine(NE)induces low-efficacy thermogenesis,evoking both heterogeneous changes(ΔΨm andΔpH)and homogenous responses,one of which is that NE stimulation causes large amounts of ATP consumption in brown adipocytes.We reveal that the proton-ATPase activity of mitochondrial complex V is a key factor that antagonizes proton leakage by UCP1 and determines the efficacy of NE-induced thermogenesis in brown adipocytes.Furthermore,to avoid unnecessary and undesired heat production,we reveal that ATP is a necessary sympathetic cotransmitter for the high efficacy and specificity of NE-induced thermogenesis in brown adipocytes as it increases intracellular calcium concentrations and upregulates the ATP synthase activity of complex V.Thus,we demonstrate the modulation mechanism of thermogenic efficacy in brown adipocytes.These findings imply new strategies to partially or fully utilize the thermogenic capacity of brown adipocytes to identify therapeutic targets for the treatment of obesity and diabetes.展开更多
文摘Neuronal atrophy is a common pathological feature occurred in aging and neurodegenerative diseases. A variety of abnormalities including motor protein mal- function and mitochondrial dysfunction contribute to the loss of neuronal architecture; however, less is known about the intracallular signaling pathways that can pro- tect against or delay this pathogenic process. Here, we show that the DYNClll deficiency, a neuron-specific dynein intermediate chain, causes neuronal atrophy in primary hippocampal neurons. With this cellular model, we are able to find that activation of RAS-RAF.MEK signaling protects against neuronal atrophy induced by DYNClll deficiency, which relies on MEK-dependent autophagy in neuron. Moreover, we further reveal that BRAF also protects against neuronal atrophy induced by mitochondrial impairment. These findings demon- strate protective roles of the RAS-RAF-MEK axis against neuronal atrophy, and imply a new therapeutic target for clinical intervention.
文摘Obesity is a worldwide epidemic and results from excessive energy intake or inefficient energy expenditure.It is promising to utilize the thermogenic function of brown adipose tissue for obesity intervention.However,the mechanisms controlling the efficacy of norepinephrine-induced thermogenesis in brown adipocytes remain elusive.Here we demonstrate that norepinephrine(NE)induces low-efficacy thermogenesis,evoking both heterogeneous changes(ΔΨm andΔpH)and homogenous responses,one of which is that NE stimulation causes large amounts of ATP consumption in brown adipocytes.We reveal that the proton-ATPase activity of mitochondrial complex V is a key factor that antagonizes proton leakage by UCP1 and determines the efficacy of NE-induced thermogenesis in brown adipocytes.Furthermore,to avoid unnecessary and undesired heat production,we reveal that ATP is a necessary sympathetic cotransmitter for the high efficacy and specificity of NE-induced thermogenesis in brown adipocytes as it increases intracellular calcium concentrations and upregulates the ATP synthase activity of complex V.Thus,we demonstrate the modulation mechanism of thermogenic efficacy in brown adipocytes.These findings imply new strategies to partially or fully utilize the thermogenic capacity of brown adipocytes to identify therapeutic targets for the treatment of obesity and diabetes.
