• Acetylation in mitochondria dynamics and neurodegeneration

      Waddell, Jaylyn; Banerjee, Aditi; Kristian, Tibor (MDPI AG, 2021-11-01)
      Mitochondria are a unique intracellular organelle due to their evolutionary origin and multifunctional role in overall cellular physiology and pathophysiology. To meet the specific spatial metabolic demands within the cell, mitochondria are actively moving, dividing, or fusing. This process of mitochondrial dynamics is fine-tuned by a specific group of proteins and their complex post-translational modifications. In this review, we discuss the mitochondrial dynamics regulatory enzymes, their adaptor proteins, and the effect of acetylation on the activity of fusion and fission machinery as a ubiquitous response to metabolic stresses. Further, we discuss the role of intracellular cytoskeleton structures and their post-translational modifications in the modulation of mitochon-drial fusion and fission. Finally, we review the role of mitochondrial dynamics dysregulation in the pathophysiology of acute brain injury and the treatment strategies based on modulation of NAD+-dependent deacetylation. © 2021 by the authors.
    • Choline Plus Working Memory Training Improves Prenatal Alcohol-Induced Deficits in Cognitive Flexibility and Functional Connectivity in Adulthood in Rats.

      Waddell, Jaylyn; Hill, Elizabeth; Tang, Shiyu; Jiang, Li; Xu, Su; Mooney, Sandra M (MDPI AG, 2020-11-14)
      Fetal alcohol spectrum disorder (FASD) is the leading known cause of intellectual disability, and may manifest as deficits in cognitive function, including working memory. Working memory capacity and accuracy increases during adolescence when neurons in the prefrontal cortex undergo refinement. Rats exposed to low doses of ethanol prenatally show deficits in working memory during adolescence, and in cognitive flexibility in young adulthood. The cholinergic system plays a crucial role in learning and memory processes. Here we report that the combination of choline and training on a working memory task during adolescence significantly improved cognitive flexibility (performance on an attentional set shifting task) in young adulthood: 92% of all females and 81% of control males formed an attentional set, but only 36% of ethanol-exposed males did. Resting state functional magnetic resonance imaging showed that functional connectivity among brain regions was different between the sexes, and was altered by prenatal ethanol exposure and by choline + training. Connectivity, particularly between prefrontal cortex and striatum, was also different in males that formed a set compared with those that did not. Together, these findings indicate that prenatal exposure to low doses of ethanol has persistent effects on brain functional connectivity and behavior, that these effects are sex-dependent, and that an adolescent intervention could mitigate some of the effects of prenatal ethanol exposure.
    • Heavy ion minibeam therapy: Side effects in normal brain

      Eley, John G.; Haga, Catherine W.; Keller, Asaf; Lazenby, Ellis M.; Raver, Charles; Rusek, Adam; Dilmanian, Farrokh Avraham; Krishnan, Sunil; Waddell, Jaylyn (MDPI AG, 2021-12-09)
      The purpose of this work was to investigate whether minibeam therapy with heavy ions might offer improvements of the therapeutic ratio for the treatment of human brain cancers. To assess neurotoxicity, we irradiated normal juvenile rats using 120 MeV lithium‐7 ions at an absorbed integral dose of 20 Gy. Beams were configured either as a solid parallel circular beam or as an array of planar parallel minibeams having 300‐micron width and 1‐mm center‐to‐center spacing within a circular array. We followed animals for 6 months after treatment and utilized behavioral testing and immunohistochemical studies to investigate the resulting cognitive impairment and chronic pathologic changes. We found both solid‐beam therapy and minibeam therapy to result in cognitive impairment compared with sham controls, with no apparent reduction in neurotoxicity using heavy ion minibeams instead of solid beams under the conditions of this study. © 2021 by the authors.
    • The Non-Specific Drp1 Inhibitor Mdivi-1 Has Modest Biochemical Antioxidant Activity

      Bordt, Evan A.; Zhang, Naibo; Waddell, Jaylyn; Polster, Brian M. (MDPI AG, 2022-03-01)
      Mitochondrial division inhibitor-1 (mdivi-1), a non-specific inhibitor of Drp1-dependent mi-tochondrial fission, is neuroprotective in numerous preclinical disease models. These include rodent models of Alzheimer’s disease and ischemic or traumatic brain injury. Among its Drp1-independent actions, the compound was found to suppress mitochondrial Complex I-dependent respiration but with less resultant mitochondrial reactive oxygen species (ROS) emission compared with the classical Complex I inhibitor rotenone. We employed two different methods of quantifying Trolox-equivalent antioxidant capacity (TEAC) to test the prediction that mdivi-1 can directly scavenge free radicals. Mdivi-1 exhibited moderate antioxidant activity in the 2,2′-azinobis (3-ethylbenzothiazoline 6-sulfonate) (ABTS) assay. Half-maximal ABTS radical depletion was observed at ~25 µM mdivi-1, equivalent to that achieved by ~12.5 µM Trolox. Mdivi-1 also showed antioxidant activity in the α, α-diphenyl-β-picrylhydrazyl (DPPH) assay. However, mdivi-1 exhibited a reduced capacity to deplete the DPPH radical, which has a more sterically hindered radical site compared with ABTS, with 25 µM mdivi-1 displaying only 0.8 µM Trolox equivalency. Both assays indicate that mdivi-1 possesses biochemical antioxidant activity but with modest potency relative to the vitamin E analog Trolox. Future studies are needed to evaluate whether the ability of mdivi-1 to directly scavenge free radicals contributes to its mechanisms of neuroprotection. © 2022 by the authors.
    • Perturbed Brain Glucose Metabolism Caused by Absent SIRT3 Activity

      Kristian, Tibor; Karimi, Arman J; Fearnow, Adam; Waddell, Jaylyn; McKenna, Mary C (MDPI AG, 2021-09-08)
      Acetylation is a post-translational modification that regulates the activity of enzymes fundamentally involved in cellular and mitochondrial bioenergetic metabolism. NAD+ dependent deacetylase sirtuin 3 (SIRT3) is localized to mitochondria where it plays a key role in regulating acetylation of TCA cycle enzymes and the mitochondrial respiratory complexes. Although the SIRT3 target proteins in mitochondria have been identified, the effect of SIRT3 activity on mitochondrial glucose metabolism in the brain remains elusive. The impact of abolished SIRT3 activity on glucose metabolism was determined in SIRT3 knockout (KO) and wild type (WT) mice injected with [1,6-13C]glucose using ex vivo 13C-NMR spectroscopy. The 1H-NMR spectra and amino acid analysis showed no differences in the concentration of lactate, glutamate, alanine, succinate, or aspartate between SIRT3 KO and WT mice. However, glutamine, total creatine (Cr), and GABA were lower in SIRT3 KO brain. Incorporation of label from [1,6-13C]glucose metabolism into lactate or alanine was not affected in SIRT3 KO brain. However, the incorporation of the label into all isotopomers of glutamate, glutamine, GABA and aspartate was lower in SIRT3 KO brain, reflecting decreased activity of mitochondrial and TCA cycle metabolism in both neurons and astrocytes. This is most likely due to hyperacetylation of mitochondrial enzymes due to suppressed SIRT3 activity in the brain of SIRT3 KO mice. Thus, the absence of Sirt3 results in impaired mitochondrial oxidative energy metabolism and neurotransmitter synthesis in the brain. Since the SIRT3 activity is NAD+ dependent, these results might parallel changes in glucose metabolism under pathologic reduction in mitochondrial NAD+ pools.
    • Telemedicine During the COVID-19 Pandemic for Pediatric Eosinophilic Esophagitis Patients

      Kewalramani, Anupama; Waddell, Jaylyn; Puppa, Elaine Leonard (Elsevier Inc., 2021-06-20)
      Eosinophilic esophagitis (EoE) is a chronic disease in which patients require long-term therapy and management by Gastroenterologists and Allergists/Immunologists1 , 2. The coronavirus disease 2019 (COVID-19) pandemic led to a shift in how physicians treat patients with increasing reliance on telemedicine (TM). As cases of COVID-19 surged in the United States and the world, TM became a mainstay of care. Even with declines in cases and medical practices having in-person (IP) visits, recommendations were made to continue TM, especially for those with lower acuity diseases such as EoE3. We are unaware of any published studies evaluating TM in the care of EoE patients. We assessed the utility of TM in the care of pediatric EoE patients during the COVID-19 pandemic.