A5058483322- Mitochondrial Function and Pathology
- Neuroscience and Neuropharmacology Research
- Genetic Neurodegenerative Diseases
- Axon Guidance and Neuronal Signaling
- Metabolism and Genetic Disorders
- Ion channel regulation and function
- ATP Synthase and ATPases Research
- Cancer, Hypoxia, and Metabolism
- Neurological disorders and treatments
- Connexins and lens biology
- Cell death mechanisms and regulation
- Alzheimer's disease research and treatments
- Muscle Physiology and Disorders
- Lipid Membrane Structure and Behavior
- Infectious Encephalopathies and Encephalitis
- Bone Metabolism and Diseases
- Hematopoietic Stem Cell Transplantation
- Adipose Tissue and Metabolism
- Neuroscience and Neural Engineering
- Cancer Research and Treatments
- Immune Cell Function and Interaction
- Neuroinflammation and Neurodegeneration Mechanisms
- Mesenchymal stem cell research
- Nicotinic Acetylcholine Receptors Study
- Cancer-related Molecular Pathways
Indiana University – Purdue University Indianapolis
2015-2025
Indiana University School of Medicine
2014-2025
Indiana University
2005-2016
Neurosciences Institute
2012-2016
University School
2012-2016
Indianapolis Zoo
2012
Pediatrics and Genetics
2012
University of Minnesota
1999-2006
University of Minnesota Medical Center
2005
Ludwig-Maximilians-Universität München
2002
Single-channel current measurements of excised patches with reconstituted purified mitochondrial ADP/ATP carrier (AAC) indicates the presence a large low cation selective (PK+/PCl− = 4.3 ± 0.6) channel. The channel conductance has multiple sublevels and varies from 300 to 600 pS. It probability fluctuations at Vhold up 80−100 mV both signs is reversibly gated > 150 mV. opening Ca2+-dependent (1 mM Ca2+) can be closed on removal Ca2+. strongly pH dependent closes completely pHex 5.2....
Abstract The mechanisms of Ca 2+ ‐induced release Cytochrome c (Cyt ) from rat brain mitochondria were examined quantitatively using a capture ELISA. In 75 or 125 m KCl‐based media 1.4 µmol /mg protein caused depolarization and mitochondrial swelling. However, this resulted in partial Cyt only KCl. was inhibited by Ru 360 , an inhibitor the uniporter, cyclosporin A plus ADP, combination permeability transition inhibitors. Transmission electron microscopy (TEM) revealed that swelling rupture...
Mutations in brain isoforms of voltage-gated sodium channels have been identified patients with distinct epileptic phenotypes. Clinically, these often do not respond well to classic anti-epileptics and many remain refractory treatment. Exogenous as endogenous cannabinoids shown target cannabidiol has recently received attention for its potential efficacy the treatment childhood epilepsies. In this study, we further investigated ability modulate currents from wild-type epilepsy-associated...
Aberrant glutamate and calcium signalings are neurotoxic to specific neuronal populations. Calcium/calmodulin-dependent kinase II (CaMKII), a multifunctional serine/threonine protein in neurons, is believed regulate neurotransmission synaptic plasticity response signaling produced by activity. Importantly, several CaMKII substrates control structure, excitability, plasticity. Here, we demonstrate that inhibition for >4 h using small molecule peptide inhibitors induces apoptosis cultured...
Mitochondria were simultaneously isolated from striatum and cortex of adult rats compared in functional assays for their sensitivity to calcium activation the permeability transition. Striatal mitochondria showed an increased dose-dependent Ca2+ with cortical mitochondria, as measured by mitochondrial depolarization, swelling, uptake, reactive oxygen species production, respiration. Ratios ATP ADP lower striatal exposed despite equal amounts under respiring nonrespiring conditions. The...
Activation of the mitochondrial permeability transition may contribute to excitotoxic neuronal death (Ankarcrona et al., 1996; Dubinsky and Levi, 1998). However, cyclosporin A (CsA), a potent inhibitor in liver mitochondria, only protects against injury by limited doses glutamate selected ischemic paradigms. The lack consistent CsA inhibition was analyzed with use isolated brain mitochondria. Changes inner membrane were evaluated monitoring potential (Deltapsi), using distribution...
Creatine and phosphocreatine were evaluated for their ability to prevent death of cultured striatal hippocampal neurons exposed either glutamate or 3‐nitropropionic acid (3NP) inhibit the mitochondrial permeability transition in CNS mitochondria. Phosphocreatine (PCr), a lesser extent creatine (Cr), but not (5R,10S)‐(+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐5,10‐imine hydrogen maleate (MK801), dose‐dependently ameliorated 3NP toxicity when applied simultaneously with Mg 2+ ‐free...
Collapsin response mediator protein 2 (CRMP2) is traditionally viewed as an axonal growth involved in axon/dendrite specification. Here, we describe novel functions of CRMP2. A 15-amino acid peptide from CRMP2, fused to the TAT cell-penetrating motif HIV-1 protein, TAT-CBD3, but not CBD3 without TAT, attenuated N-methyl-d-aspartate receptor (NMDAR) activity and protected neurons against glutamate-induced Ca(2+) dysregulation, suggesting key contribution CRMP2 these processes. In addition, or...
Isolated brain mitochondria were examined for their responses to calcium challenges under varying conditions. Mitochondrial membrane potential was monitored by following the distribution of tetraphenylphosphonium ions in mitochondrial suspension, swelling observing absorbance changes, accumulation an external electrode, and oxygen consumption with electrode. Both extent rate calcium-induced depolarization varied greatly depending on energy source provided mitochondria. When energized...
Strong support for the central role of ADP/ATP carrier (AAC) in mitochondrial permeability transition (mPT) is provided by single-channel current measurements patch-clamp experiments with isolated reconstituted AAC. In previous work [Brustovetsky, N., and Klingenberg, M. (1996) Biochemistry 35, 8483−8488], this technique was applied to AAC from bovine heart mitochondria. Here we used recombinant (rAAC) Neurospora crassa expressed E. coli, since mammalian sources cannot be expresssed coli....
Abstract Striatal and cortical mitochondria from knock‐in transgenic mutant huntingtin mice were examined for their sensitivity to calcium induction of the permeability transition, a cause mitochondrial depolarization ATP loss. The transition has been suggested contribute cell death in Huntington's Disease. Mitochondria slowly progressing mouse models with different length polyglutarnine expansions (Q20, Q50, Q92, Q111) rapidly R6/2 overexpressing exon I human more than 110 polyglutamines....
We previously reported that destruction of the small ubiquitin-like modifier (SUMO) modification site in axonal collapsin response mediator protein 2 (CRMP2) was sufficient to selectively decrease trafficking voltage-gated sodium channel NaV1.7 and reverse neuropathic pain. Here, we further interrogate biophysical nature interaction between CRMP2 SUMOylation machinery, test hypothesis a rationally designed motif (CSM) peptide can interrupt E2 SUMO-conjugating enzyme Ubc9-dependent leading...
Ca2+ influx into mitochondria is mediated by the mitochondrial calcium uniporter (MCU), whose identity was recently revealed as a 40-kDa protein that along with other proteins forms uptake machinery. The MCU Ca2+-conducting channel spanning inner membrane. Here, deletion of completely inhibited in liver, heart, and skeletal muscle mitochondria. However, brain nonsynaptic synaptic from neuronal somata/glial cells nerve terminals, respectively, slowed, but did not block, uptake. Under resting...
An exposure of cultured hippocampal neurons expressing mitochondrially targeted enhanced yellow fluorescent protein to excitotoxic glutamate resulted in reversible mitochondrial remodeling that many instances could be interpreted as swelling. Remodeling was not evident if receptors were blocked with MK801, Ca(2+) omitted or substituted for Sr(2+) the bath solution, treated carbonylcyanide p-trifluoromethoxyphenylhydrazone depolarize mitochondria, pretreated cyclosporin A...
Abstract Delayed calcium deregulation (DCD) plays an essential role in glutamate excitotoxicity, a major detrimental factor stroke, traumatic brain injury, and various neurodegenerations. In the present study, we examined of calpain activation Na + /Ca 2+ exchanger (NCX) degradation DCD excitotoxic cell death cultured hippocampal neurons. Exposure neurons to caused accompanied by secondary mitochondrial depolarization. Activation was evidenced detecting NCX isoform 3 (NCX3) products....
An isothiourea derivative (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methane sulfonate (KB-R7943), a widely used inhibitor of the reverse Na(+) /Ca(2+) exchanger (NCX(rev)), was instrumental in establishing role NCX(rev) glutamate-induced Ca(2+) deregulation neurons. Here, effects KB-R7943 on N-methyl-D-aspartate (NMDA) receptors and mitochondrial complex I were tested.Fluorescence microscopy, electrophysiological patch-clamp techniques cellular respirometry with Seahorse XF24...
We investigated Ca(2+) handling in isolated brain synaptic and non-synaptic mitochondria cultured striatal neurons from the YAC128 mouse model of Huntington's disease. Both 2- 12-month-old mice had larger uptake capacity than YAC18 wild-type FVB/NJ mice. Synaptic further augmented compared with 2-month-old age-matched This increase correlated an amount mutant huntingtin protein (mHtt) associated speculate that this may happen because mHtt-mediated sequestration free fatty acids thereby...