Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability o...Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability or dysfunction may be the key stimulating factors to activate NLRP3 inflammasome,and sustained Ca^(2+)transfer can result in mitochondrial dysfunction.We focused on KCs to explore the damage to mitochondria by EA.After EA stimulation,cells produced an oxidative stress(OS)response with a significant increase in ROS release.Immunoprecipitation experiments and the addition of inhibitors revealed that the increase in the level of intracellular Ca^(2+)led to Ca^(2+)accumulation in the mitochondrial matrix via mitochondria-associated membranes(MAMs).This was accompanied by a significant release of m ROS,loss of MMP and ATP,and a significant increase in mitochondrial permeability transition pore opening,ultimately leading to mitochondrial instability.These findings confirmed the mechanism that EA induced mitochondrial Ca^(2+)imbalance in KCs via MAM,ultimately leading to mitochondrial dysfunction.Meanwhile,EA induced OS and the decrease of MMP and ATP in rat liver,and significant lesions were found in liver mitochondria.Swelling of the inner mitochondrial cristae and mitochondrial vacuolization occurred,with a marked increase in lipid droplets.展开更多
Traumatic spinal cord injuries interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. This interruption results in either temporary or permanent alterations in ...Traumatic spinal cord injuries interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. This interruption results in either temporary or permanent alterations in the locomotor, sensory, and autonomic functions. Damage in the spinal tissue prevents the re-growth of severed axons across the lesion and their reconnection with neuronal targets. Therefore, the absence of spontaneous repair leads to sustained impairment in voluntary control of movement below the injury. For decades, axonal regeneration and reconnection have been considered the opitome of spinal cord injury repair with the goal being the repair of the damaged long motor and sensory tracts in a complex process that involves:(1) resealing injured axons;(2) reconstructing the cytoskeletal structure inside axons;(3) re-establishing healthy growth cones;and(4) assembling axonal cargos. These biological processes require an efficient production of adenosine triphosphate, which is affected by mitochondrial dysfunction after spinal cord injury. From a pathological standpoint, during the secondary stage of spinal cord injury, mitochondrial homeostasis is disrupted, mainly in the distal segments of severed axons. This result in a reduction of adenosine triphosphate levels and subsequent inactivation of adenosine triphosphate-dependent ion pumps required for the regulation of ion concentrations and reuptake of neurotransmitters, such as glutamate. The consequences are calcium overload, reactive oxygen species formation, and excitotoxicity. These events are intimately related to the activation of necrotic and apoptotic cell death programs, and further exacerbate the secondary stage of the injury, being a hallmark of spinal cord injury. This is why restoring mitochondrial function during the early stage of secondary injury could represent a potentially effective therapeutic intervention to overcome the motor and sensory failure produced by spinal cord injury. This review discusses the most recent evidence linking mitochondrial dysfunction with axonal regeneration failure in the context of spinal cord injury. It also covers the future of mitochondria-targeted therapeutical approaches, such as antioxidant molecules, removing mitochondrial anchor proteins, and increasing energetic metabolism through creatine treatment. These approaches are intended to enhance functional recovery by promoting axonal regenerationreconnection after spinal cord injury.展开更多
Mitochondrial dysfunction is proposed to be substantially associated with ageing and ageing-related diseases like Alzheimer's disease(AD). However, it is unclear whether different mouse models with mitochondrialre...Mitochondrial dysfunction is proposed to be substantially associated with ageing and ageing-related diseases like Alzheimer's disease(AD). However, it is unclear whether different mouse models with mitochondrialrelated diseases have similar changes in mitochondrial morphology of the same tissues. Moreover, whether similarities in mitochondrial morphology can be a suitable marker for screening and/or discovering mitochondrial-protective substances remains unknown. Mitochondria morphology in different tissues of a novel mitochondrial outer membrane protein Slc25a46 knockout mouse and a traditional APP_(SWE)/PS1ΔE9 transgenic mouse were examined using transmission electron microscope(TEM). Both young Slc25a46 knockout mice and aged APP_(SWE)/PS1ΔE9 mice models showed similar mitochondrial damage in cerebellum tissues. The results indicated that different mitochondrial-related diseases shared similar alteration and defects in mitochondrial morphology. Furthermore, Lycium ruthenicum Murr. extract, a bioactive food substance with cognition-improving property, could effectively improve muscle strength and increase body weight in the Slc25a46 knockout mice. These findings suggest that mitochondrial morphology defects in mice models, particularly in the mitochondrial compartment, represent a unified and effective marker for screening and validating natural product-derived functional substances with mitochondrial protective properties. It also holds potential application in mitochondrial-impaired senile neurodegenerative diseases, especially in AD.展开更多
Mitochondrial dysfunction increases ROS production and is closely related to many degenerative cellular organelle diseases.The NOX4-p22phox axis is a major contributor to ROS production and its dysregulation is expect...Mitochondrial dysfunction increases ROS production and is closely related to many degenerative cellular organelle diseases.The NOX4-p22phox axis is a major contributor to ROS production and its dysregulation is expected to disrupt mitochondrial function.However,the field lacks a competitive inhibitor of the NOX4-p22phox interaction.Here,we created a povidone micelle-based Prussian blue nanozyme that we named“Mitocelle”to target the NOX4-p22phox axis,and characterized its impact on the major degenerative cellular organelle disease,osteoarthritis(OA).Mitocelle is composed of FDA-approved and biocompatible materials,has a regular spherical shape,and is approximately 88 nm in diameter.Mitocelle competitively inhibits the NOX4-p22phox interaction,and its uptake by chondrocytes can protect against mitochondrial malfunction.Upon intra-articular injection to an OA mouse model,Mitocelle shows long-term stability,effective uptake into the cartilage matrix,and the ability to attenuate joint degradation.Collectively,our findings suggest that Mitocelle,which functions as a competitive inhibitor of NOX4-p22phox,may be suitable for translational research as a therapeutic for OA and cellular organelle diseases related to dysfunctional mitochondria.展开更多
In recent years,the roles of mitochondrial RNA and its associated human diseases have been reported to increase significantly.Treatments based on mtRNA metabolic processes and nuclear gene mutations are thus discussed...In recent years,the roles of mitochondrial RNA and its associated human diseases have been reported to increase significantly.Treatments based on mtRNA metabolic processes and nuclear gene mutations are thus discussed.The mitochondrial oxidative phosphorylation process is affected by mtRNA metabolism,including mtRNA production,maturation,stabilization,and degradation,which leads to a variety of inherited human mitochondrial diseases.Moreover,mitochondrial diseases are caused by mitochondrial messenger RNA,mitochondrial transfer RNA,and mitochondrial ribosomal RNA gene mutations.This review presents the molecular mechanisms of human mtRNA metabolism and pathological mutations in mtRNA metabolism-related nuclear-encoded/nonencoded genes and mitochondrial DNA mutations to highlight the importance of mitochondrial RNA-related diseases and treatments.展开更多
Background:Cholestasis plays a critical role in sepsis-associated liver injury(SALI).Intestine-derived fibroblast growth factor 19(FGF19)is a key regulator for bile acid homeostasis.However,the roles and underlying me...Background:Cholestasis plays a critical role in sepsis-associated liver injury(SALI).Intestine-derived fibroblast growth factor 19(FGF19)is a key regulator for bile acid homeostasis.However,the roles and underlying mechanisms of FGF19 in SALI are still unclear.Methods:We conducted a case-control study that included 58 pediatric patients aged from 1 month to 14-years-old diagnosed with sepsis at Shanghai Children’s Hospital from January to December 2018 and 30 healthy individuals.The serum FGF19 levels of these patients with sepsis were analyzed and compared with those of healthy controls.Recombinant human FGF19 was intravenously injected in mice once a day for 7 days at a dose of 0.1 mg/kg body weight before lipopolysaccharide(LPS)treatment.Liver bile acid profiles and the gene expression involved in bile acid homeostasis were investigated in the mice groups.Metabolomic data were further integrated and analyzed using Ingenuity Pathways Analysis(IPA)software.In the in vitro analysis using HepG2 cells,the influence of FGF19 pretreatment on reactive oxygen species(ROS)production and mitochondrial dysfunction was analyzed.Compound C(CC),an inhibitor of AMP-activated protein kinase(AMPK)activation,was used to confirm the roles of AMPK activation in FGF19-mediated hepatoprotective effects.Results:Serum FGF19 levels were significantly lower in children with sepsis than in healthy controls(115 pg/mL vs.79 pg/mL,P=0.03).Pre-administration of recombinant human FGF19 alleviated LPS-induced acute liver injury(ALI)and improved LPS-induced cholestasis in mice.Moreover,FGF19 directly reversed LPS-induced intracellular ROS generation and LPS-decreased mitochondrial membrane potential in vitro and in vivo,resulting in hepatoprotection against LPS-induced apoptosis.More importantly,the inhibition of AMPK activity partially blocked the protective effects of FGF19 against LPS-induced oxidative stress and mitochondrial dysfunction.Conclusions:Intestine-derived FGF19 alleviates LPS-induced ALI via improving bile acid homeostasis and directly suppressing ROS production via activating the AMPK signaling pathway.展开更多
Lung cancer continues to be the second most common cancer diagnosed and the main cause of cancer-related death globally,which requires novel and effective treatment strategies.When considering treatment options,non-sm...Lung cancer continues to be the second most common cancer diagnosed and the main cause of cancer-related death globally,which requires novel and effective treatment strategies.When considering treatment options,non-small cell lung cancer(NSCLC)remained a challenge,seeking new therapeutic strategies.High-power microwave(HPM)progressions have facilitated the advancement of new technologies as well as improvements to those al-ready in use.The impact of HPM on NSCLC has not been investigated before.In this work,we uncovered the effect of pulsed HPM on NSCLC(H460 and A549)for the first time and the most likely underlying mechanisms.Two NSCLC(H460 and A549)cells and lung normal MRC5 were exposed to HPM(15,30,45,and 60)pulses(2.1 mJ/pulse).After exposure,the effects were observed at 12,24,48,and 72 h.HPM primarily increases the level of intracellular reactive species by a strong electric field of∼27 kV/cm,which altered NSCLC viability,mitochondrial activity,and death rates.A model for the production of intracellular reactive species by HPM was also presented.NSCLC is found to be affected by HPM through DNA damage(upregulation of ATR/ATM,Chk1/Chk2,and P53)and increased expression of apoptotic markers.NAC scavenger and CPTIO-inhibitor confirm that the reactive species are mainly accountable for cellular effects.In order to ensure suitability for real-world usage,the skin depth was calculated as 30 mm.ROS played a main role in inducing cellular effects,with NO species possibly play-ing a contributing role.These findings clarify the cellular mechanisms underlying HPM-induced cell death,poten-tially advancing therapeutic approaches for treating NSCLC,and a useful first step for future investigations in this area.Moreover,this technique has the potential to serve as an adjunct to non-surgical methods in cancer therapy.展开更多
基金supported by fund from the National Natural Science Foundation of China(32172322)。
文摘Elaidic acid(EA)stimulation can lead to endoplasmic reticulum stress(ERS),accompanied by a large release of Ca^(2+),and ultimately the activation of NLRP3 inflammasome in Kupffer cells(KCs).Mitochondrial instability or dysfunction may be the key stimulating factors to activate NLRP3 inflammasome,and sustained Ca^(2+)transfer can result in mitochondrial dysfunction.We focused on KCs to explore the damage to mitochondria by EA.After EA stimulation,cells produced an oxidative stress(OS)response with a significant increase in ROS release.Immunoprecipitation experiments and the addition of inhibitors revealed that the increase in the level of intracellular Ca^(2+)led to Ca^(2+)accumulation in the mitochondrial matrix via mitochondria-associated membranes(MAMs).This was accompanied by a significant release of m ROS,loss of MMP and ATP,and a significant increase in mitochondrial permeability transition pore opening,ultimately leading to mitochondrial instability.These findings confirmed the mechanism that EA induced mitochondrial Ca^(2+)imbalance in KCs via MAM,ultimately leading to mitochondrial dysfunction.Meanwhile,EA induced OS and the decrease of MMP and ATP in rat liver,and significant lesions were found in liver mitochondria.Swelling of the inner mitochondrial cristae and mitochondrial vacuolization occurred,with a marked increase in lipid droplets.
基金supported by a grant from PICT2019-N°01665 to HRQ
文摘Traumatic spinal cord injuries interrupt the connection of all axonal projections with their neuronal targets below and above the lesion site. This interruption results in either temporary or permanent alterations in the locomotor, sensory, and autonomic functions. Damage in the spinal tissue prevents the re-growth of severed axons across the lesion and their reconnection with neuronal targets. Therefore, the absence of spontaneous repair leads to sustained impairment in voluntary control of movement below the injury. For decades, axonal regeneration and reconnection have been considered the opitome of spinal cord injury repair with the goal being the repair of the damaged long motor and sensory tracts in a complex process that involves:(1) resealing injured axons;(2) reconstructing the cytoskeletal structure inside axons;(3) re-establishing healthy growth cones;and(4) assembling axonal cargos. These biological processes require an efficient production of adenosine triphosphate, which is affected by mitochondrial dysfunction after spinal cord injury. From a pathological standpoint, during the secondary stage of spinal cord injury, mitochondrial homeostasis is disrupted, mainly in the distal segments of severed axons. This result in a reduction of adenosine triphosphate levels and subsequent inactivation of adenosine triphosphate-dependent ion pumps required for the regulation of ion concentrations and reuptake of neurotransmitters, such as glutamate. The consequences are calcium overload, reactive oxygen species formation, and excitotoxicity. These events are intimately related to the activation of necrotic and apoptotic cell death programs, and further exacerbate the secondary stage of the injury, being a hallmark of spinal cord injury. This is why restoring mitochondrial function during the early stage of secondary injury could represent a potentially effective therapeutic intervention to overcome the motor and sensory failure produced by spinal cord injury. This review discusses the most recent evidence linking mitochondrial dysfunction with axonal regeneration failure in the context of spinal cord injury. It also covers the future of mitochondria-targeted therapeutical approaches, such as antioxidant molecules, removing mitochondrial anchor proteins, and increasing energetic metabolism through creatine treatment. These approaches are intended to enhance functional recovery by promoting axonal regenerationreconnection after spinal cord injury.
基金supported by National Key R&D Program of China (2018YFD0901101)the Natural Science Foundation of Guangdong Province Research (2019A1515012230)+1 种基金Development Program in Key Areas of Guangdong Province (2019B020210002)the Fundamental Research Funds for the Central Universities (2019KZ01)。
文摘Mitochondrial dysfunction is proposed to be substantially associated with ageing and ageing-related diseases like Alzheimer's disease(AD). However, it is unclear whether different mouse models with mitochondrialrelated diseases have similar changes in mitochondrial morphology of the same tissues. Moreover, whether similarities in mitochondrial morphology can be a suitable marker for screening and/or discovering mitochondrial-protective substances remains unknown. Mitochondria morphology in different tissues of a novel mitochondrial outer membrane protein Slc25a46 knockout mouse and a traditional APP_(SWE)/PS1ΔE9 transgenic mouse were examined using transmission electron microscope(TEM). Both young Slc25a46 knockout mice and aged APP_(SWE)/PS1ΔE9 mice models showed similar mitochondrial damage in cerebellum tissues. The results indicated that different mitochondrial-related diseases shared similar alteration and defects in mitochondrial morphology. Furthermore, Lycium ruthenicum Murr. extract, a bioactive food substance with cognition-improving property, could effectively improve muscle strength and increase body weight in the Slc25a46 knockout mice. These findings suggest that mitochondrial morphology defects in mice models, particularly in the mitochondrial compartment, represent a unified and effective marker for screening and validating natural product-derived functional substances with mitochondrial protective properties. It also holds potential application in mitochondrial-impaired senile neurodegenerative diseases, especially in AD.
基金supported by the National Research Foundation,funded by the Ministry of Science&ICT(2021M3C1C3097647,NRF-2022R1A2C2004343,RS-2023-00223552,and RS-2024-00335111)the Korea Healthcare Technology R&D project of the Korea Health Industry Development Institute(HI16C0001 and HR22C1734)+1 种基金a Korean Fund for Regenerative Medicine(KFRM)grant funded by the Korea government(the Ministry of Science and ICT,the Ministry of Health&Welfare,23C0113L1)the Korea Institute of Ceramic Engineering and Technology(KICET,2410002182).
文摘Mitochondrial dysfunction increases ROS production and is closely related to many degenerative cellular organelle diseases.The NOX4-p22phox axis is a major contributor to ROS production and its dysregulation is expected to disrupt mitochondrial function.However,the field lacks a competitive inhibitor of the NOX4-p22phox interaction.Here,we created a povidone micelle-based Prussian blue nanozyme that we named“Mitocelle”to target the NOX4-p22phox axis,and characterized its impact on the major degenerative cellular organelle disease,osteoarthritis(OA).Mitocelle is composed of FDA-approved and biocompatible materials,has a regular spherical shape,and is approximately 88 nm in diameter.Mitocelle competitively inhibits the NOX4-p22phox interaction,and its uptake by chondrocytes can protect against mitochondrial malfunction.Upon intra-articular injection to an OA mouse model,Mitocelle shows long-term stability,effective uptake into the cartilage matrix,and the ability to attenuate joint degradation.Collectively,our findings suggest that Mitocelle,which functions as a competitive inhibitor of NOX4-p22phox,may be suitable for translational research as a therapeutic for OA and cellular organelle diseases related to dysfunctional mitochondria.
文摘In recent years,the roles of mitochondrial RNA and its associated human diseases have been reported to increase significantly.Treatments based on mtRNA metabolic processes and nuclear gene mutations are thus discussed.The mitochondrial oxidative phosphorylation process is affected by mtRNA metabolism,including mtRNA production,maturation,stabilization,and degradation,which leads to a variety of inherited human mitochondrial diseases.Moreover,mitochondrial diseases are caused by mitochondrial messenger RNA,mitochondrial transfer RNA,and mitochondrial ribosomal RNA gene mutations.This review presents the molecular mechanisms of human mtRNA metabolism and pathological mutations in mtRNA metabolism-related nuclear-encoded/nonencoded genes and mitochondrial DNA mutations to highlight the importance of mitochondrial RNA-related diseases and treatments.
基金supported by the National Natural Science Foundation of China(grant number:82171729)the Natural Science Foundation of Shanghai(grant number:23ZR1453000)+1 种基金the Shanghai Municipal Health Commission(grant number:202340076)the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant(grant number:20171928).
文摘Background:Cholestasis plays a critical role in sepsis-associated liver injury(SALI).Intestine-derived fibroblast growth factor 19(FGF19)is a key regulator for bile acid homeostasis.However,the roles and underlying mechanisms of FGF19 in SALI are still unclear.Methods:We conducted a case-control study that included 58 pediatric patients aged from 1 month to 14-years-old diagnosed with sepsis at Shanghai Children’s Hospital from January to December 2018 and 30 healthy individuals.The serum FGF19 levels of these patients with sepsis were analyzed and compared with those of healthy controls.Recombinant human FGF19 was intravenously injected in mice once a day for 7 days at a dose of 0.1 mg/kg body weight before lipopolysaccharide(LPS)treatment.Liver bile acid profiles and the gene expression involved in bile acid homeostasis were investigated in the mice groups.Metabolomic data were further integrated and analyzed using Ingenuity Pathways Analysis(IPA)software.In the in vitro analysis using HepG2 cells,the influence of FGF19 pretreatment on reactive oxygen species(ROS)production and mitochondrial dysfunction was analyzed.Compound C(CC),an inhibitor of AMP-activated protein kinase(AMPK)activation,was used to confirm the roles of AMPK activation in FGF19-mediated hepatoprotective effects.Results:Serum FGF19 levels were significantly lower in children with sepsis than in healthy controls(115 pg/mL vs.79 pg/mL,P=0.03).Pre-administration of recombinant human FGF19 alleviated LPS-induced acute liver injury(ALI)and improved LPS-induced cholestasis in mice.Moreover,FGF19 directly reversed LPS-induced intracellular ROS generation and LPS-decreased mitochondrial membrane potential in vitro and in vivo,resulting in hepatoprotection against LPS-induced apoptosis.More importantly,the inhibition of AMPK activity partially blocked the protective effects of FGF19 against LPS-induced oxidative stress and mitochondrial dysfunction.Conclusions:Intestine-derived FGF19 alleviates LPS-induced ALI via improving bile acid homeostasis and directly suppressing ROS production via activating the AMPK signaling pathway.
基金supported by the National Research Foundation of Korea(NRF)with grants funded by the Korean government(MIST)(NRF-2022R1A2C1004257,NRF-2021R1A6A1A03038785)Kwangwoon University,Seoul,Korea,2023.
文摘Lung cancer continues to be the second most common cancer diagnosed and the main cause of cancer-related death globally,which requires novel and effective treatment strategies.When considering treatment options,non-small cell lung cancer(NSCLC)remained a challenge,seeking new therapeutic strategies.High-power microwave(HPM)progressions have facilitated the advancement of new technologies as well as improvements to those al-ready in use.The impact of HPM on NSCLC has not been investigated before.In this work,we uncovered the effect of pulsed HPM on NSCLC(H460 and A549)for the first time and the most likely underlying mechanisms.Two NSCLC(H460 and A549)cells and lung normal MRC5 were exposed to HPM(15,30,45,and 60)pulses(2.1 mJ/pulse).After exposure,the effects were observed at 12,24,48,and 72 h.HPM primarily increases the level of intracellular reactive species by a strong electric field of∼27 kV/cm,which altered NSCLC viability,mitochondrial activity,and death rates.A model for the production of intracellular reactive species by HPM was also presented.NSCLC is found to be affected by HPM through DNA damage(upregulation of ATR/ATM,Chk1/Chk2,and P53)and increased expression of apoptotic markers.NAC scavenger and CPTIO-inhibitor confirm that the reactive species are mainly accountable for cellular effects.In order to ensure suitability for real-world usage,the skin depth was calculated as 30 mm.ROS played a main role in inducing cellular effects,with NO species possibly play-ing a contributing role.These findings clarify the cellular mechanisms underlying HPM-induced cell death,poten-tially advancing therapeutic approaches for treating NSCLC,and a useful first step for future investigations in this area.Moreover,this technique has the potential to serve as an adjunct to non-surgical methods in cancer therapy.
