Browsing by Subject "Adenosine diphosphate"

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    Mitochondrial uncouplers induce proton leak by activating AAC and UCP1
    (Springer Nature, 2022) Bertholet, Ambre M.; Natale, Andrew M.; Bisignano, Paola; Suzuki, Junji; Fedorenko, Andriy; Hamilton, James; Brustovetsky, Tatiana; Kazak, Lawrence; Garrity, Ryan; Chouchani, Edward T.; Brustovetsky, Nickolay; Grabe, Michael; Kirichok, Yuriy; Pharmacology and Toxicology, School of Medicine
    Mitochondria generate heat due to H+ leak (IH) across their inner membrane1. IH results from the action of long-chain fatty acids on uncoupling protein 1 (UCP1) in brown fat2-6 and ADP/ATP carrier (AAC) in other tissues1,7-9, but the underlying mechanism is poorly understood. As evidence of pharmacological activators of IH through UCP1 and AAC is lacking, IH is induced by protonophores such as 2,4-dinitrophenol (DNP) and cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP)10,11. Although protonophores show potential in combating obesity, diabetes and fatty liver in animal models12-14, their clinical potential for treating human disease is limited due to indiscriminately increasing H+ conductance across all biological membranes10,11 and adverse side effects15. Here we report the direct measurement of IH induced by DNP, FCCP and other common protonophores and find that it is dependent on AAC and UCP1. Using molecular structures of AAC, we perform a computational analysis to determine the binding sites for protonophores and long-chain fatty acids, and find that they overlap with the putative ADP/ATP-binding site. We also develop a mathematical model that proposes a mechanism of uncoupler-dependent IH through AAC. Thus, common protonophoric uncouplers are synthetic activators of IH through AAC and UCP1, paving the way for the development of new and more specific activators of these two central mediators of mitochondrial bioenergetics.
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    Viscoelastic Testing and Coagulopathy of Traumatic Brain Injury
    (MDPI, 2021-10-28) Bradbury, Jamie L.; Thomas, Scott G.; Sorg, Nikki R.; Mjaess, Nicolas; Berquist, Margaret R.; Brenner, Toby J.; Langford, Jack H.; Marsee, Mathew K.; Moody, Ashton N.; Bunch, Connor M.; Sing, Sandeep R.; Al-Fadhl, Mahmoud D.; Salamah, Qussai; Saleh, Tarek; Patel, Neal B.; Shaikh, Kashif A.; Smith, Stephen M.; Langheinrich, Walter S.; Fulkerson, Daniel H.; Sixta, Sherry; Neurological Surgery, School of Medicine
    A unique coagulopathy often manifests following traumatic brain injury, leading the clinician down a difficult decision path on appropriate prophylaxis and therapy. Conventional coagulation assays—such as prothrombin time, partial thromboplastin time, and international normalized ratio—have historically been utilized to assess hemostasis and guide treatment following traumatic brain injury. However, these plasma-based assays alone often lack the sensitivity to diagnose and adequately treat coagulopathy associated with traumatic brain injury. Here, we review the whole blood coagulation assays termed viscoelastic tests and their use in traumatic brain injury. Modified viscoelastic tests with platelet function assays have helped elucidate the underlying pathophysiology and guide clinical decisions in a goal-directed fashion. Platelet dysfunction appears to underlie most coagulopathies in this patient population, particularly at the adenosine diphosphate and/or arachidonic acid receptors. Future research will focus not only on the utility of viscoelastic tests in diagnosing coagulopathy in traumatic brain injury, but also on better defining the use of these tests as evidence-based and/or precision-based tools to improve patient outcomes.