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p17/C18-ceramide-mediated mitophagy is an endogenous neuroprotective response in preclinical and clinical brain injury.
Karakaya, Eda; Oleinik, Natalia; Edwards, Jazlyn; Tomberlin, Jensen; Barker, Randy Bent; Berber, Burak; Ericsson, Maria; Alsudani, Habeeb; Ergul, Adviye; Beyaz, Semir; Lemasters, John J; Ogretmen, Besim; Albayram, Onder.
Afiliação
  • Karakaya E; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Oleinik N; Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Edwards J; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Tomberlin J; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Barker RB; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Berber B; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Ericsson M; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Alsudani H; Department of Biology, Eskisehir Technical University, Tepebasi/Eskisehir 26555, Turkey.
  • Ergul A; Electron Microscopy Laboratory, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Beyaz S; Cancer Center, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
  • Lemasters JJ; College of Science, University of Basrah, Basra 61004, Iraq.
  • Ogretmen B; Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
  • Albayram O; Ralph H. Jackson Department of Veterans Affairs Medical Center, Charleston, SC 29425, USA.
PNAS Nexus ; 3(2): pgae018, 2024 Feb.
Article em En | MEDLINE | ID: mdl-38328780
ABSTRACT
Repeat concussions (or repetitive mild traumatic brain injury [rmTBI]) are complex pathological processes consisting of a primary insult and long-term secondary complications and are also a prerequisite for chronic traumatic encephalopathy (CTE). Recent evidence implies a significant role of autophagy-mediated dysfunctional mitochondrial clearance, mitophagy, in the cascade of secondary deleterious events resulting from TBI. C18-ceramide, a bioactive sphingolipid produced in response to cell stress and damage, and its synthesizing enzyme (CerS1) are precursors to selective stress-mediated mitophagy. A transporter, p17, mediates the trafficking of CerS1, induces C18-ceramide synthesis in the mitochondrial membrane, and acts as an elimination signal in cell survival. Whether p17-mediated mitophagy occurs in the brain and plays a causal role in mitochondrial quality control in secondary disease development after rmTBI are unknown. Using a novel repetitive less-than-mild TBI (rlmTBI) injury paradigm, ablation of mitochondrial p17/C18-ceramide trafficking in p17 knockout (KO) mice results in a loss of C18-ceramide-induced mitophagy, which contributes to susceptibility and recovery from long-term secondary complications associated with rlmTBI. Using a ceramide analog with lipid-selenium conjugate drug, LCL768 restored mitophagy and reduced long-term secondary complications, improving cognitive deficits in rlmTBI-induced p17KO mice. We obtained a significant reduction of p17 expression and a considerable decrease of CerS1 and C18-ceramide levels in cortical mitochondria of CTE human brains compared with age-matched control brains. These data demonstrated that p17/C18-ceramide trafficking is an endogenous neuroprotective mitochondrial stress response following rlmTBI, thus suggesting a novel prospective strategy to interrupt the CTE consequences of concussive TBI.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article