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John J Lemasters - One of the best experts on this subject based on the ideXlab platform.
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role of Mitochondrial permeability transition pores in Mitochondrial autophagy
The International Journal of Biochemistry & Cell Biology, 2004Co-Authors: Sara Rodriguezenriquez, Lihua He, John J LemastersAbstract:Abstract During autophagy, cells rid themselves of damaged and superfluous Mitochondria, as well as other organelles. This activation of Mitochondrial turnover could be the result of changes in the physiological state of Mitochondria. Confocal microscopy and fluorescence techniques indicate that onset of Mitochondrial permeability transition is one such change. The Mitochondrial permeability transition is a reversible phenomenon whereby the Mitochondrial inner membrane becomes freely permeable to solutes of less than 1500 Da. At onset of the Mitochondrial permeability transition, Mitochondria depolarize, uncouple, and undergo large amplitude swelling due to opening of permeability transition pores, which may form by aggregation of damaged, misfolded membrane proteins. When injurious cellular stresses occur, cells may protect themselves using autophagy to remove damaged Mitochondria and mutated Mitochondrial DNA. Ca 2+ overloading, reactive oxygen and nitrogen species, decreased Mitochondrial membrane potential, and oxidation of pyridine nucleotides and glutathione all promote Mitochondrial damage and onset of the Mitochondrial permeability transition. The Mitochondrial permeability transition is also associated with necrosis and apoptosis after a variety of stimuli. This review emphasizes the role of the Mitochondrial permeability transition as a key event in Mitochondrial autophagy.
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the Mitochondrial permeability transition initiates autophagy in rat hepatocytes
The FASEB Journal, 2001Co-Authors: Steven P Elmore, Ting Qian, Sherry F Grissom, John J LemastersAbstract:SPECIFIC AIMSWe set out to determine the relationship between Mitochondrial depolarization, induction of the Mitochondrial permeability transition, and Mitochondrial autophagy in rat hepatocytes stimulated by glucagon and nutrient deprivation.PRINICIPAL FINDINGS1. Autophagic stimulation induces Mitochondrial depolarizationThe fluorophores MitoTracker Green (MTG) and tetramethylrhodamine ethylester (TMRM) both accumulate into polarized Mitochondria, but only TMRM is released after depolarization. Since TMRM quenches MTG fluorescence by fluorescence resonance energy transfer (FRET), release of TMRM from Mitochondria after depolarization leads to unquenching of green MTG fluorescence. Thus, MTG fluorescence uniquely identifies newly depolarized Mitochondria. Using this technique, we showed that autophagic stimulation of rat hepatocytes with glucagon and nutrient deprivation caused a fivefold increase in depolarized Mitochondria (see Figs. 1⤻ and 2⤻ ). Figure 1.Entry of spontaneously depolarizing Mitochondria...
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contribution of the Mitochondrial permeability transition to lethal injury after exposure of hepatocytes to t butylhydroperoxide
Biochemical Journal, 1995Co-Authors: Anna Liisa Nieminen, A K Saylor, Samuel A Tesfai, Brian Herman, John J LemastersAbstract:Abstract We have developed a novel method for monitoring the Mitochondrial permeability transition in single intact hepatocytes during injury with t-butylhydroperoxide (t-BuOOH). Cultured hepatocytes were loaded with the fluorescence probes, calcein and tetramethylrhodamine methyl ester (TMRM). Depending on loading conditions, calcein labelled the cytosolic space exclusively and did not enter Mitochondria or it stained both cytosol and Mitochondria. TMRM labelled Mitochondria as an indicator of Mitochondrial polarization. Fluorescence of two probes was imaged simultaneously using laser-scanning confocal microscopy. During normal incubations, TMRM labelled Mitochondria indefinitely (longer than 63 min), and calcein did not redistribute between cytosol and Mitochondria. These findings indicate that the Mitochondrial permeability transition pore ('megachannel') remained closed continuously. After addition of 100 microM t-BuOOH, Mitochondria filled quickly with calcein, indicating the onset of Mitochondrial permeability transition. This event was accompanied by Mitochondrial depolarization, as shown by loss of TMRM. Subsequently, the concentration of ATP declined and cells lost viability. Trifluoperazine, a phospholipase inhibitor that inhibits the permeability transition in isolated Mitochondria, prevented calcein redistribution into Mitochondria, Mitochondrial depolarization, ATP depletion and cell death. Carbonyl cyanide m-chlorophenylhydrazone (CCCP), a Mitochondrial uncoupler, also rapidly depolarized Mitochondria of intact hepatocytes but did not alone induce a permeability transition. Trifluoperazine did not prevent ATP depletion and cell death after the addition of CCCP. In conclusion, the permeability transition pore does not 'flicker' open during normal incubation of hepatocytes but remains continuously closed. Moreover, Mitochondrial depolarization per se does not cause the permeability transition in intact cells. During oxidative stress, however, a permeability transition occurs quickly which leads to Mitochondrial depolarization and cell death.
Hemachandra P Reddy - One of the best experts on this subject based on the ideXlab platform.
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mutant huntingtin s interaction with Mitochondrial protein drp1 impairs Mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in huntington s disease
Human Molecular Genetics, 2012Co-Authors: Ulziibat P Shirendeb, Marcus J Calkins, Maria Manczak, Hemachandra P Reddy, Vishwanath Anekonda, Brett D Dufour, Jodi L McbrideAbstract:The purpose of this study was to investigate the link between mutant huntingtin (Htt) and neuronal damage in relation to Mitochondria in Huntington's disease (HD). In an earlier study, we determined the relationship between mutant Htt and Mitochondrial dynamics/synaptic viability in HD patients. We found Mitochondrial loss, abnormal Mitochondrial dynamics and mutant Htt association with Mitochondria in HD patients. In the current study, we sought to expand on our previous findings and further elucidate the relationship between mutant Htt and Mitochondrial and synaptic deficiencies. We hypothesized that mutant Htt, in association with Mitochondria, alters Mitochondrial dynamics, leading to Mitochondrial fragmentation and defective axonal transport of Mitochondria in HD neurons. In this study, using postmortem HD brains and primary neurons from transgenic BACHD mice, we identified mutant Htt interaction with the Mitochondrial protein Drp1 and factors that cause abnormal Mitochondrial dynamics, including GTPase Drp1 enzymatic activity. Further, using primary neurons from BACHD mice, for the first time, we studied axonal transport of Mitochondria and synaptic degeneration. We also investigated the effect of mutant Htt aggregates and oligomers in synaptic and Mitochondrial deficiencies in postmortem HD brains and primary neurons from BACHD mice. We found that mutant Htt interacts with Drp1, elevates GTPase Drp1 enzymatic activity, increases abnormal Mitochondrial dynamics and results in defective anterograde Mitochondrial movement and synaptic deficiencies. These observations support our hypothesis and provide data that can be utilized to develop therapeutic targets that are capable of inhibiting mutant Htt interaction with Drp1, decreasing Mitochondrial fragmentation, enhancing axonal transport of Mitochondria and protecting synapses from toxic insults caused by mutant Htt.
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impaired Mitochondrial biogenesis defective axonal transport of Mitochondria abnormal Mitochondrial dynamics and synaptic degeneration in a mouse model of alzheimer s disease
Human Molecular Genetics, 2011Co-Authors: Marcus J Calkins, Maria Manczak, Peizhong Mao, Ulziibat P Shirendeb, Hemachandra P ReddyAbstract:Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic Mitochondria causes synaptic Mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of Aβ in Mitochondrial activity and synaptic alterations in neurons from a mouse model of AD. Using primary neurons from a well-characterized Aβ precursor protein transgenic (AβPP) mouse model (Tg2576 mouse line), for the first time, we studied Mitochondrial activity, including axonal transport of Mitochondria, Mitochondrial dynamics, morphology and function. Further, we also studied the nature of Aβ-induced synaptic alterations, and cell death in primary neurons from Tg2576 mice, and we sought to determine whether the Mitochondria-targeted antioxidant SS31 could mitigate the effects of oligomeric Aβ. We found significantly decreased anterograde Mitochondrial movement, increased Mitochondrial fission and decreased fusion, abnormal Mitochondrial and synaptic proteins and defective Mitochondrial function in primary neurons from AβPP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed a large number of small Mitochondria and structurally damaged Mitochondria, with broken cristae in AβPP primary neurons. We also found an increased accumulation of oligomeric Aβ and increased apoptotic neuronal death in the primary neurons from the AβPP mice relative to the WT neurons. Our results revealed an accumulation of intraneuronal oligomeric Aβ, leading to Mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in AβPP cultures. However, we found that the Mitochondria-targeted antioxidant SS31 restored Mitochondrial transport and synaptic viability, and decreased the percentage of defective Mitochondria, indicating that SS31 protects Mitochondria and synapses from Aβ toxicity.
Huawei Liang - One of the best experts on this subject based on the ideXlab platform.
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effect of activation of Mitochondrial atp sensitive potassium channel and calcium activated potassium channel on the permeability transition of Mitochondria from both normal and ischemic rat brain
Chinese journal of applied physiology, 2007Co-Authors: Fang Shen, Liping Wu, Yan Lu, Huawei LiangAbstract:AIM: To clarify whether the activation of Mitochondrial ATP sensitive potassium channel and calcium activated potassium channel can influence the permeability transition of normal and ischemic brain Mitochondria. METHODS: spectrophotometry was used to determine the effect of the two Mitochondrial potassium channel agonists on the swelling of normal and ischemic brain Mitochondria respectively. RESULTS: In normal Mitochondria, diazoxide and NS1619 could inhibit the decrease of calcium induced Mitochondrial absorbance at 520 nm (A520), which were blocked by atractyloside. When compared with the normal Mitochondria, Mitochondrial A520 decrease in ischemic brain was even more rapid. Diazoxide and NS1619 could still inhibit the calcium induced Mitochondrial A520 decrease, which were blocked by atractyloside. CONCLUSION: Activation of Mitochondrial ATP sensitive potassium channel and calcium activated potassium channel can protect brain Mitochondria in vitro probably via influencing the Mitochondrial permeability transition.
Fang Shen - One of the best experts on this subject based on the ideXlab platform.
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effect of activation of Mitochondrial atp sensitive potassium channel and calcium activated potassium channel on the permeability transition of Mitochondria from both normal and ischemic rat brain
Chinese journal of applied physiology, 2007Co-Authors: Fang Shen, Liping Wu, Yan Lu, Huawei LiangAbstract:AIM: To clarify whether the activation of Mitochondrial ATP sensitive potassium channel and calcium activated potassium channel can influence the permeability transition of normal and ischemic brain Mitochondria. METHODS: spectrophotometry was used to determine the effect of the two Mitochondrial potassium channel agonists on the swelling of normal and ischemic brain Mitochondria respectively. RESULTS: In normal Mitochondria, diazoxide and NS1619 could inhibit the decrease of calcium induced Mitochondrial absorbance at 520 nm (A520), which were blocked by atractyloside. When compared with the normal Mitochondria, Mitochondrial A520 decrease in ischemic brain was even more rapid. Diazoxide and NS1619 could still inhibit the calcium induced Mitochondrial A520 decrease, which were blocked by atractyloside. CONCLUSION: Activation of Mitochondrial ATP sensitive potassium channel and calcium activated potassium channel can protect brain Mitochondria in vitro probably via influencing the Mitochondrial permeability transition.
Roberto Cereijo-santaló - One of the best experts on this subject based on the ideXlab platform.
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The effect of nonelectrolytes on the 2,4-dinitrophenol-activated ATPase of rat liver Mitochondria.
Archives of Biochemistry and Biophysics, 2004Co-Authors: Roberto Cereijo-santalóAbstract:Abstract The ATPase activity and swelling of rat liver Mitochondria have been studied in different nonelectrolyte media. Twenty-three polyhydroxylic compounds, with molecular weight ranging from 92 to 504, were tested. It was found that as the molecular size of the nonelectrolytes decrease (and the lipid/water partition coefficient increases) mitochoadria tend to swell. The activation of ATPase by DNP appears to be independent of the kind of nonelectrolyte present in the medium. The activation of ATPase by gramicidin increases as swelling increases. It is suggested that gramicidin increases the permeability to Tris, especially in swollen Mitochondria. It was found that the inhibition of the DNP-activated ATPase by valinomycin or gramicidin takes place only in contracted Mitochondria and it can be prevented by the presence in the medium of alkali metal cations. When Mitochondrial swelling occurs the inhibition does not take place.
