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MKT-077 normalizes mitochondrial function and mitigates cardiac pathology in mdx mice

BIOCELL 2024年第12期48卷 1815-1825页

作者： MIKHAIL V.DUBININ IRINA B.MIKHEEVA ANASTASIA E.STEPANOVA NATALIA V.MIKINA DANIIL V.SUSHENTSOV VYACHESLAV A.SHARAPOV ALENA A.CHEREPANOVA VALENTIN V.LOSKUTOV KONSTANTIN N.BELOSLUDTSEV Department of Biochemistry Cell Biologyand MicrobiologyMari State UniversityYoshkar-Ola424001Russia laboratory of mitochondrial transport Institute of Theoretical and Experimental BiophysicsRussian Academy of SciencesPushchino142290Russia

Objectives:Duchenne muscular dystrophy(DMD)is characterized by the development of cardiac pathology secondarily expressed in mitochondrial *** treatment includes support for mitochondrial *** purpose of this work was to evaluate the effects of the lipophilic cation MKT-077,capable of modulating mitochondrial activity,on the structure and function of cardiac mitochondria in mdx and wild-type mice,as well as the state of this ***:Animals were divided into 4 groups:wild type(WT),WT+5 mg/kg MKT-077,mdx,mdx+5 mg/kg ***-077 was administered intraperitoneally daily for 28 ***,we assessed the parameters of the functioning of the cardiac mitochondria of mice,the expression of genes encoding proteins involved in mitochondrial communication,as well as the histology and ultrastructure of the myocardium and heart ***:MKT-077 was shown to reverse mitochondrial hyperfunctionalization in mdx mice,reducing respiratory parameters to WT ***-077 also inhibited mitochondrial respiration in the hearts of WT ***-077 administration was accompanied by a tendency to normalize calcium retention capacity in the cardiac mitochondria of mdx *** ultrastructure and gene signature of mdx+MKT077 animals demonstrated increased *** noted changes in the sarcoplasmic reticulum(SR)/mitochondria contacts,accompanied by differential changes in the level of genes encoding proteins involved in the communication of these *** effect of MKT-077 was accompanied by normalization of the relative heart weight of mdx mice,a decrease in the level of fibrosis,and a tendency toward normalization of heart ***:MKT-077-induced reversal of cardiac mitochondrial hyperfunctionalization in mdx mice may promote a healthy-like state of the myocardium in these animals.

关键词： Duchenne muscular dystrophy mdx mice Cardiac mitochondria MKT-077

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mitochondrial electron transport chain is involved in microcystin-RR induced tobacco BY-2 cells apoptosis

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Journal of Environmental Sciences 2014年第9期26卷 1930-1935页

作者： Wenmin Huang Dunhai Li Yongding Liu Key laboratory of Algal Biology Institute of HydrobiologyChinese Academy of Sciences Key laboratory of Aquatic Botany and Watershed Ecology Wuhan Botanical Gardenthe Chinese Academy of Sciences

Microcystin-RR （MC-RR） has been suggested to induce apoptosis in tobacco BY-2 cells through mitochondrial dysfunction including the loss of mitochondrial membrane potential . TO further elucidate the mechanisms involved in MC-RR induced apoptosis in tobacco BY-2 cells, we have investigated the role of mitochondrial electron transport chain （ETC） as a potential source for reactive oxygen species （ROS）. Tobacco BY-2 cells after exposure to MC-RR （60 mg/L） displayed apoptotic changes in association with an increased production of ROS and loss of Am. All of these adverse effects were significantly attenuated by ETC inhibitors including Rotenone （2 μmol/L, complex I inhibitor） and antimycin A （0.01 μmol/L, complex III inhibitor）, but not by thenoyltrifluoroacetone （S μmol/L, complex Ⅱinhibitor）. These results suggest that rnitochondrial ETC plays a key role in mediating MC-RR induced apoptosis in tobacco BY-2 cells through an increased mitochondrial production of ROS.

关键词： Microcystin-RRTobacco BY-2 cellsApoptosisReactive oxygen speciesmitochondrial electron transport chain

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SNX14 deficiency-induced defective axonal mitochondrial transport in Purkinje cells underlies cerebellar ataxia and can be reversed by valproate

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National Science Review 2021年第7期8卷 72-85页

作者： Hongfeng Zhang Yujuan Hong Weijie Yang Ruimin Wang Ting Yao Jian Wang Ke Liu Huilong Yuan Chaoqun Xu Yuanyuan Zhou Guanxian Li Lishan Zhang Hong Luo Xian Zhang Dan Du Hao Sun Qiuyang Zheng Yun-Wu Zhang Yingjun Zhao Ying Zhou Huaxi Xu Xin Wang State Key laboratory of Cellular Stress Biology Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research Institute of Neuroscience School of Medicine Xiamen University National Institute for Data Science in Health and Medicine School of Medicine Xiamen University Cancer Research Center Department of Stomatology School of Medicine Xiamen University

Loss-of-function mutations in sorting nexin 14(SNX14) cause autosomal recessive spinocerebellar ataxia20, which is a form of early-onset cerebellar ataxia that lacks molecular mechanisms and mouse models. We generated Snx14-deficient mouse models and observed severe motor deficits and cell-autonomous Purkinje cell degeneration. SNX14 deficiency disrupted microtubule organization and mitochondrial transport in axons by destabilizing the microtubule-severing enzyme spastin, which is implicated in dominant hereditary spastic paraplegia with cerebellar ataxia, and compromised axonal integrity and mitochondrial function. Axonal transport disruption and mitochondrial dysfunction further led to degeneration of highenergy-demanding Purkinje cells, which resulted in the pathogenesis of cerebellar ataxia. The antiepileptic drug valproate ameliorated motor deficits and cerebellar degeneration in Snx14-deficient mice via the restoration of mitochondrial transport and function in Purkinje cells. Our study revealed an unprecedented role for SNX14-dependent axonal transport in cerebellar ataxia, demonstrated the convergence of SNX14 and spastin in mitochondrial dysfunction, and suggested valproate as a potential therapeutic agent.

关键词： sorting nexin 14 cerebellar ataxia Purkinje cell degeneration mitochondrial dysfunction axonal transport valproate

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Variants within KIF5B are associated with weight loss through mitochondrial transport alteration in sheep

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Journal of Genetics and Genomics 2024年第12期51卷 1513-1516页

作者： Jieran Chen Haitao Wang Tingting Li Yuting Zhang Yan Chen Na Zhang Hengqian Yang Zhichao Zhang Ziyuan Duan Xia Li Daxiang Wang Zhixiong He Fan Hu Jianfeng Gao Runlin Z.Ma Xun Huang Qiuyue Liu College of Life Sciences Shihezi UniversityShiheziXinjiang 832000China State Key laboratory of Molecular Developmental Biology Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijing 100101China Jiangsu Qianbao Animal Husbandry Co. LtdYanchengJiangsu 224050China CAS Key laboratory for Agro-Ecological Processes in Subtropical Region National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry ProductionHunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic ProcessInstitute of Subtropical AgricultureChinese Academy of SciencesChangshaHunan 410125China

Sheep(Ovis aries)is a key source of meat for humans,and their weight loss significantly impacts meat *** a few causative genes related to weight loss have been identified,the inheritance mechanisms and genetic pathways involved remain to be further *** selection can effectively fix substantial mutations in these genes,enhancing meat production in *** family member 5B(KIF5B)is a member of the kinesin-1protein family,which is made up of two kinesin heavy chains(KHCs)and two kinesin light chains(KLCs).Each kinesin motor head features an ATP pocket and a microtubule-binding domain,enabling it to function as a molecular motor(Hirokawa et al.,2009).

关键词： chains weight sheep

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Modulation of the matrix redox signaling by mitochondrial Ca^(2+)

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World Journal of Biological Chemistry 2015年第4期6卷 310-323页

作者： Jaime Santo-Domingo Andreas Wiederkehr Umberto De Marchi mitochondrial Function Nestlé Institute of Health Sciences

Mitochondria sense,shape and integrate signals,and thus function as central players in cellular signal transduction. Ca2+ waves and redox reactions are two such intracellular signals modulated by mitochondria. mitochondrial Ca2+ transport is of utmost physio-pathological relevance with a strong impact on metabolism and cell fate. Despite its importance,the molecular nature of the proteins involvedin mitochondrial Ca2+ transport has been revealed only recently. mitochondrial Ca2+ promotes energy metabolism through the activation of matrix dehydrogenases and downstream stimulation of the respiratory chain. These changes also alter the mitochondrial NAD(P)H/NAD(P)+ ratio,but at the same time will increase reactive oxygen species(ROS) production. Reducing equivalents and ROS are having opposite effects on the mitochondrial redox state,which are hard to dissect. With the recent development of genetically encoded mitochondrial-targeted redoxsensitive sensors,real-time monitoring of matrix thiol redox dynamics has become possible. The discoveries of the molecular nature of mitochondrial transporters of Ca2+ combined with the utilization of the novel redox sensors is shedding light on the complex relation between mitochondrial Ca2+ and redox signals and their impact on cell function. In this review,we describe mitochondrial Ca2+ handling,focusing on a number of newly identified proteins involved in mitochondrial Ca2+ uptake and release. We further discuss our recent findings,revealing how mitochondrial Ca2+ influences the matrix redox state. As a result,mitochondrial Ca2+ is able to modulate the many mitochondrial redox-regulated processes linked to normal physiology and disease.

关键词： Calcium transport Signal transduction Redox regula

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Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke:a special outlook on mitochondrial delivery

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Neural Regeneration Research 2025年第8期20卷 2181-2198页

作者： Jiali Chen Yiyang Li Xingping Quan Jinfen Chen Yan Han Li Yang Manfei Zhou Greta Seng Peng Mok Ruibing Wang Yonghua Zhao Institute of Chinese Medical Sciences State Key Laboratory of Quality Research in Chinese MedicineUniversity of MacaoTaipaMacao Special Administrative RegionChina Department of Pharmacy Hunan Provincial People’s Hospitalthe First Affiliated Hospital of Hunan Normal UniversityChangshaHunan ProvinceChina Department of Electrical and Computer Engineering University of MacaoTaipaMacao Special Administrative RegionChina Department of Pharmaceutical Sciences Faculty of Health SciencesUniversity of MacaoTaipaMacao Special Administrative RegionChina

Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on *** vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic ***,the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery *** utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles,their delivery efficacy may be greatly ***,previous studies have indicated that microvesicles,a subset of large-sized extracellular vesicles,can transport mitochondria to neighboring cells,thereby aiding in the restoration of mitochondrial function post-ischemic *** extracellular vesicles have also demonstrated the capability to transfer mitochondrial components,such as proteins or deoxyribonucleic acid,or their sub-components,for extracellular vesicle-based ischemic stroke *** this review,we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification *** the complex facets of treating ischemic stroke,we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment ***,given the burgeoning interest in mitochondrial delivery,we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

关键词： delivery engineering extracellular vesicles identification ischemic stroke isolation mitochondria targeting strategy therapeutic effects

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Optical redox imaging of ANT1-de-cient muscles

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Journal of Innovative Optical Health Sciences 2024年第1期17卷 135-140页

作者： He N.Xu Ryan M.Morrow Min Feng Huaqing Zhao Douglas Wallace Lin Z.Li Britton Chance laboratory of Redox Imaging Department of Radiology Perelman School of Medicine University of Pennsylvania PhiladelphiaPA 19104USA Center for mitochondrial and Epigenomic Medicine Children's Hospital of Philadelphia Research Institute Philadelphia PA 19104USA Center for Biostatistics and Epidemiology Lewis Katz School of Medicine at Temple University Philadelphia PA 19140USA

Adenine nucleotide translocator(ANT)is a mitochondrial protein involved in the exchange of ADP and ATP across the mitochondrial inner *** plays a crucial role in cellular energy metabolism by facilitating the transport of ATP synthesized within the mitochondria to the *** isoform ANT1 predominately expresses in cardiac and skeletal *** or dysregulation in ANT1 have been implicated in various mitochondrial disorders and neuromuscular *** aimed to examine whether ANT1 deletion may affect mitochondrial redox state in our established ANT1-de-cient *** and quadriceps resected from age-matched wild type(WT)and ANT1-de-cient mice were snap-frozen in liquid *** Chance redox scanner was utilized to perform 3D optical redox *** sample underwent scanning across 3–5 *** averaging analysis showed no signi-cant differences in the redox indices(NADH,flavin adenine dinucleotide containing-flavoproteins Fp,and the redox ratio Fp/(NADH+Fp)between WT and ANT1-de-cient ***,quadriceps had higher Fp than hearts in both groups(p¼0:0004 and 0.01,respectively).Furthermore,the quadriceps were also more oxidized(a higher redox ratio)than hearts in WT group(p¼0:004).NADH levels were similar in all *** data suggest that under non-stressful physical condition,the ANT1-de-cient muscle cells were in the same mitochondrial state as WT ones and that the signi-cant difference in the mitochondrial redox state between quadriceps and hearts found in WT might be diminished in ANT1-de-cient *** imaging of muscles under physical stress can be conducted in future.

关键词： ANT1 redox ratio flavoproteins

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Advanced nerve regeneration enabled by neural conformal electronic stimulators enhancing mitochondrial transport

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Bioactive Materials 2024年第9期39卷 287-301页

作者： Hao Bai Siqi Zhang Huiran Yang Jing Wang Hongli Chen Jia Li Lin Li Qian Yang Bo Peng Ziyi Zhu Siyuan Ni Keyin Liu Wei Lei Tiger H.Tao Yafei Feng Department of Orthopedics Xijing HospitalThe Fourth Military Medical UniversityXi’an710032China State Key laboratory of Transducer Technology Shanghai Institute of Microsystem and Information TechnologyChinese Academy of SciencesShanghai200050China Key laboratory of Aerospace Medicine of the Ministry of Education School of Aerospace MedicineFourth Military Medical UniversityXi’anChina The Institute of Flexible Electronics(IFE Future Technologies)Xiamen UniversityXiamen361005FujianChina Frontiers Science Center for Flexible Electronics Xi’an Institute of Flexible Electronics(IFE)and Xi’an Institute of Biomedical Materials&EngineeringNorthwestern Polytechnical UniversityXi’an710072PR China Center of Materials Science and Optoelectronics Engineering University of Chinese Academy of SciencesBeijing100049China School of Physical Science and Technology ShanghaiTech UniversityShanghai200031China Institute of Brain-Intelligence Technology Zhangjiang LaboratoryShanghai200031China

Addressing peripheral nerve defects remains a significant challenge in regenerative *** as the gold-standard management,however,are hindered by limited availability and potential *** recent studies report the potential of wireless electronic system for nerve defects ***,few has met clinical needs for inadequate electrode precision,poor nerve entrapment andinsufficient bioactivity of the matrix ***,we present an advanced wireless electrical nerve stimulator,based on water-responsive self-curling silk membrane with excellent bioabsorbable and *** constructed a unique bilayer structure with an oriented pre-stretched inner layer and a generalsilk membrane as outer *** wetting,the simultaneous contraction of inner layer and expansion of outerlayer achieved controllable super-contraction from 2D flat surface to 3D structural *** enablesshape-adaptive wrapping to cover around nerves,overcomes the technical obstacle of preparing electrodes on theinner wall of the conduit,and prevents electrode breakage caused by material expansion in *** use of forkcapacitor-like metal interface increases the contact points between the metal and the regenerating nerve,solvingthe challenge of inefficient and rough electrical stimulation methods in the *** developed electronicstimulator is effective in restoring 10 mm rat sciatic nerve defects comparable to autologous *** underlyingmechanism involves that electric stimulation enhances anterograde mitochondrial transport to matchenergy *** newly introduced device thereby demonstrated the potential as a viable and efficaciousalternative to autografts for enhancing peripheral nerve repair and functional recovery.

关键词： Silk materials Electronic stimulator Structural reconfiguration Peripheral nerve regeneration mitochondrial transport

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mitochondrial Ca^(2+) transport and permeability transition pore opening and mitochondrial energetic status

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Science China(Life Sciences) 2000年第5期43卷 489-497页

作者：黄行许翟大勇黄有国杨福愉 National laboratory of Biomacromolecules Institute of Biophysics Chinese Academy of Sciences Beijing 100101China

The relationship between mitochondrial Ca2+ transport and permeability transition pore (PTP) opening as well as the effects of mitochondrial energetic status on mitochondrial Ca2+ transport and PTP opening were studied. The results showed that the calcium-induced calcium release from mitochondria (mClCR) induced PTP opening. Inhibitors for electron transport of respiratory chain inhibited mClCR and PTP opening. Partial recovery of electron transport in respiratory chain resulted in partial recovery of mClCR and PTP opening. mClCR and PTP opening were also inhibited by CCCP which eliminated transmembrane proton gradient. The results indicated that mitochondrial Ca2+ transport and PTP opening are largely dependent on electron transport and energy coupling.

关键词： mitochondrial Ca^(2+) transport permeability transition pore electron transport energy coupling.

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Heat stress reduces boar sperm motility via activation of glycogen synthase kinase-3α and inhibition of mitochondrial protein transport

Heat stress reduces boar sperm motility via activation of gl...

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中国生理学会内分泌代谢、比较生理与应激生理学术会议

作者： Yabin Gong Huiduo Guo Hao Zhou Bin He Ruqian Zhao Key laboratory of Animal Physiology and Biochemistry Ministry of AgricultureNanjing Agricultural University

Objective The adverse effects of heat stress(HS) on animal reproductive functions have been extensively *** synthase kinase-3α(GSK3α) is a protein kinase that sensitive to stress,plays a crucial role in sperm ***,we tested whether and how GSK3α regulates sperm motility under *** The sperm motility,mitochondrial activity and bioenergetics were determined by sperm quality analyzer,flow cytometry and transmission electron *** intracellular and mitochondrial levels of mitochondrial proteins were determined by western blot and immunofluorescence ***(1) HS induced significant decrease in sperm motility and viability as well as mitochondrial activity and adenosine triphosphate(ATP) contents.(2) Exogenous ATP abolishes the effects suggested that block of ATP synthesis is the committed step in HS-induced reduction of sperm motility.(3) The mitochondrial protein contents were significantly decreased in HS ***,the cytochrome c oxidase subunit 4(COX4),which was synthesized in cytoplasm and translocated into mitochondria,was significantly lower in mitochondria of HS sperm.(4) The GSK3αinhibitor CHIR99021 was able to abolish all the effects of HS on *** HS affects sperm motility through downregulation of mitochondrial activity and *** dephosphorylation of GSK3α and interference of mitochondrial remodeling involved in the mechanisms.

关键词： Heat stress Glycogen synthase kinase-3α Electron transport chain Oxidative phosphorylation mitochondrial remodeling Sperm

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