A decline in the activities of oxidative phosphorylation(OXPHOS)complexes has been consistently reported in amyotrophic lateral sclerosis(ALS)patients and animal models of ALS,although the underlying molecular mechani...A decline in the activities of oxidative phosphorylation(OXPHOS)complexes has been consistently reported in amyotrophic lateral sclerosis(ALS)patients and animal models of ALS,although the underlying molecular mechanisms are still elusive.Here,we report that receptor expression enhancing protein 1(REEP1)acts as an important regulator of complex IV assembly,which is pivotal to preserving motor neurons in SOD1^(G93A) mice.We found the expression of REEP1 was greatly reduced in transgenic SOD1^(G93A) mice with ALS.Moreover,forced expression of REEP1 in the spinal cord extended the lifespan,decelerated symptom progression,and improved the motor performance of SOD1^(G93A) mice.The neuromuscular synaptic loss,gliosis,and even motor neuron loss in SOD1^(G93A) mice were alleviated by increased REEP1 through augmentation of mitochondrial function.Mechanistically,REEP1 associates with NDUFA4,and plays an important role in preserving the integrity of mitochondrial complex IV.Our findings offer insights into the pathogenic mechanism of REEP1 deficiency in neurodegenerative diseases and suggest a new therapeutic target for ALS.展开更多
The generation of cellular energy in the form of ATP occurs mainly in mitochondria by oxidative phosphorylation.Cytochrome c oxidase(CytOx),the oxygen accepting and rate-limiting step of the respiratory chain,regulate...The generation of cellular energy in the form of ATP occurs mainly in mitochondria by oxidative phosphorylation.Cytochrome c oxidase(CytOx),the oxygen accepting and rate-limiting step of the respiratory chain,regulates the supply of variable ATP demands in cells by“allosteric ATP-inhibition of CytOx.”This mechanism is based on inhibition of oxygen uptake of CytOx at high ATP/ADP ratios and low ferrocytochrome c concentrations in the mitochondrial matrix via cooperative interaction of the two substrate binding sites in dimeric CytOx.The mechanism keeps mitochondrial membrane potentialΔΨm and reactive oxygen species(ROS)formation at low healthy values.Stress signals increase cytosolic calcium leading to Ca^2+-dependent dephosphorylation of CytOx subunit I at the cytosolic side accompanied by switching off the allosteric ATPinhibition and monomerization of CytOx.This is followed by increase ofΔΨm and formation of ROS.A hypothesis is presented suggesting a dynamic change of binding of NDUFA4,originally identified as a subunit of complex I,between monomeric CytOx(active state with highΔΨm,high ROS and low efficiency)and complex I(resting state with lowΔΨm,low ROS and high efficiency).展开更多
基金supported by Shandong Key R&D Program Funding(2018GSF118037)the Shandong Natural Science Foundation(ZR2019JQ24).
文摘A decline in the activities of oxidative phosphorylation(OXPHOS)complexes has been consistently reported in amyotrophic lateral sclerosis(ALS)patients and animal models of ALS,although the underlying molecular mechanisms are still elusive.Here,we report that receptor expression enhancing protein 1(REEP1)acts as an important regulator of complex IV assembly,which is pivotal to preserving motor neurons in SOD1^(G93A) mice.We found the expression of REEP1 was greatly reduced in transgenic SOD1^(G93A) mice with ALS.Moreover,forced expression of REEP1 in the spinal cord extended the lifespan,decelerated symptom progression,and improved the motor performance of SOD1^(G93A) mice.The neuromuscular synaptic loss,gliosis,and even motor neuron loss in SOD1^(G93A) mice were alleviated by increased REEP1 through augmentation of mitochondrial function.Mechanistically,REEP1 associates with NDUFA4,and plays an important role in preserving the integrity of mitochondrial complex IV.Our findings offer insights into the pathogenic mechanism of REEP1 deficiency in neurodegenerative diseases and suggest a new therapeutic target for ALS.
文摘The generation of cellular energy in the form of ATP occurs mainly in mitochondria by oxidative phosphorylation.Cytochrome c oxidase(CytOx),the oxygen accepting and rate-limiting step of the respiratory chain,regulates the supply of variable ATP demands in cells by“allosteric ATP-inhibition of CytOx.”This mechanism is based on inhibition of oxygen uptake of CytOx at high ATP/ADP ratios and low ferrocytochrome c concentrations in the mitochondrial matrix via cooperative interaction of the two substrate binding sites in dimeric CytOx.The mechanism keeps mitochondrial membrane potentialΔΨm and reactive oxygen species(ROS)formation at low healthy values.Stress signals increase cytosolic calcium leading to Ca^2+-dependent dephosphorylation of CytOx subunit I at the cytosolic side accompanied by switching off the allosteric ATPinhibition and monomerization of CytOx.This is followed by increase ofΔΨm and formation of ROS.A hypothesis is presented suggesting a dynamic change of binding of NDUFA4,originally identified as a subunit of complex I,between monomeric CytOx(active state with highΔΨm,high ROS and low efficiency)and complex I(resting state with lowΔΨm,low ROS and high efficiency).
