Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surfa...Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.展开更多
Bcl-xL is a pro-survival protein of the Bcl2 family found in the mitochondrial membrane.Bcl-xL supports growth,development,and maturation of neurons,and it also prevents neuronal death during neurotoxic stimulation.Th...Bcl-xL is a pro-survival protein of the Bcl2 family found in the mitochondrial membrane.Bcl-xL supports growth,development,and maturation of neurons,and it also prevents neuronal death during neurotoxic stimulation.This article reviews the mechanisms and upstream signaling that regulate the activity and abundance of Bcl-xL.Our team and others have reported that oxidative stress is a key regulator of intracellular Bcl-xL balance in neurons.Oxidative stress regulates synthesis,degradation,and activity of Bcl-xL and therefore neuronal function.During apoptosis,pro-apoptotic Bcl2 proteins such as Bax and Bak translocate to and oligomerize in the mitochondrial membrane.Formation of oligomers causes release of cytochrome c and activation of caspases that lead to neuronal death.Bcl-xL binds directly to pro-apoptotic Bcl2 proteins to block apoptotic signaling.Although anti-apoptotic roles of Bcl-xL have been well documented,an increasing number of studies in recent decades show that protein binding partners of Bcl-xL are not limited to Bcl2 proteins.Bcl-xL forms a complex with F1Fo ATP synthase,DJ-1,DRP1,IP3R,and the ryanodine receptor.These proteins support physiological processes in neurons such as growth and development and prevent neuronal damage by regulating mitochondrial ATP production,synapse formation,synaptic vesicle recycling,neurotransmission,and calcium signaling.However,under conditions of oxidative stress,Bcl-xL undergoes proteolytic cleavage thus lowering the abundance of functional Bcl-xL in neurons.Additionally,oxidative stress alters formation of Bcl-xL-mediated multiprotein complexes by regulating post-translational phosphorylation.Finally,oxidative stress regulates transcription factors that target the Bcl-x gene and alter accessibility of microRNA to mRNA influencing mRNA levels of Bcl-xL.In this review,we discussed how Bcl-xL supports the normal physiology of neurons,and how oxidative stress contributes to pathology by manipulating the dynamics of Bcl-xL production,degradation,and activity.展开更多
基金Supported by An INSERM Avenir Grant (Martinez LO)ANR (Martinez LO and Lichtenstein L, #GENO 102 01)+1 种基金the French Association pour la Recherche sur le Cancer (Vantourout P and Champagne E, #3711-3913-4847)An INSERM young scientist fellowship (Pons V)
文摘Mitochondrial ATP synthase has been recently detected at the surface of different cell types, where it is a high affinity receptor for apoA-I, the major protein component in high density lipoproteins (HDL). Cell surface ATP synthase (namely ecto-F1-ATPase) expression is related to different biological effects, such as regulation of HDL uptake by hepatocytes, endothelial cell proliferation or antitumor activity of Vγ9/Vδ2 T lymphocytes. This paper reviews the recently discovered functions and regulations of ecto-F1-ATPase. Particularly, the role of the F1-ATPase pathway(s) in HDL-cholesterol uptake and apoA-Imediated endothelial protection suggests its potential importance in reverse cholesterol transport and its regulation might represent a potential therapeutic target for HDL-related therapy for cardiovascular diseases. Therefore, it is timely for us to better understand how this ecto-enzyme and downstream pathways are regulated and to develop pharmacologic interventions.
文摘Bcl-xL is a pro-survival protein of the Bcl2 family found in the mitochondrial membrane.Bcl-xL supports growth,development,and maturation of neurons,and it also prevents neuronal death during neurotoxic stimulation.This article reviews the mechanisms and upstream signaling that regulate the activity and abundance of Bcl-xL.Our team and others have reported that oxidative stress is a key regulator of intracellular Bcl-xL balance in neurons.Oxidative stress regulates synthesis,degradation,and activity of Bcl-xL and therefore neuronal function.During apoptosis,pro-apoptotic Bcl2 proteins such as Bax and Bak translocate to and oligomerize in the mitochondrial membrane.Formation of oligomers causes release of cytochrome c and activation of caspases that lead to neuronal death.Bcl-xL binds directly to pro-apoptotic Bcl2 proteins to block apoptotic signaling.Although anti-apoptotic roles of Bcl-xL have been well documented,an increasing number of studies in recent decades show that protein binding partners of Bcl-xL are not limited to Bcl2 proteins.Bcl-xL forms a complex with F1Fo ATP synthase,DJ-1,DRP1,IP3R,and the ryanodine receptor.These proteins support physiological processes in neurons such as growth and development and prevent neuronal damage by regulating mitochondrial ATP production,synapse formation,synaptic vesicle recycling,neurotransmission,and calcium signaling.However,under conditions of oxidative stress,Bcl-xL undergoes proteolytic cleavage thus lowering the abundance of functional Bcl-xL in neurons.Additionally,oxidative stress alters formation of Bcl-xL-mediated multiprotein complexes by regulating post-translational phosphorylation.Finally,oxidative stress regulates transcription factors that target the Bcl-x gene and alter accessibility of microRNA to mRNA influencing mRNA levels of Bcl-xL.In this review,we discussed how Bcl-xL supports the normal physiology of neurons,and how oxidative stress contributes to pathology by manipulating the dynamics of Bcl-xL production,degradation,and activity.
