Bioenergetic restoration and neuroprotection after therapeutic targeting of mitoNEET: New mechanism of pioglitazone following traumatic brain injury

Heather M. Yonutas, W. Brad Hubbard, Jignesh D. Pandya, Hemendra J. Vekaria, Werner J. Geldenhuys, Patrick G. Sullivan

Research output: Contribution to journalReview articlepeer-review

30 Scopus citations

Abstract

Mitochondrial dysfunction is a pivotal event in many neurodegenerative disease states including traumatic brain injury (TBI) and spinal cord injury (SCI). One possible mechanism driving mitochondrial dysfunction is glutamate excitotoxicity leading to Ca2+-overload in neuronal or glial mitochondria. Therapies that reduce calcium overload and enhance bioenergetics have been shown to improve neurological outcomes. Pioglitazone, an FDA approved compound, has shown neuroprotective properties following TBI and SCI, but the underlying mechanism(s) are unknown. We hypothesized that the interaction between pioglitazone and a novel mitochondrial protein called mitoNEET was the basis for neuroprotection following CNS injury. We discovered that mitoNEET is an important mediator of Ca2+-mediated mitochondrial dysfunction and show that binding mitoNEET with pioglitazone can prevent Ca2+-induced dysfunction. By utilizing wild-type (WT) and mitoNEET null mice, we show that pioglitazone mitigates mitochondrial dysfunction and provides neuroprotection in WT mice, though produces no restorative effects in mitoNEET null mice. We also show that NL-1, a novel mitoNEET ligand, is neuroprotective following TBI in both mice and rats. These results support the crucial role of mitoNEET for mitochondrial bioenergetics, its importance in the neuropathological sequelae of TBI and the necessity of mitoNEET for pioglitazone-mediated neuroprotection. Since mitochondrial dysfunction is a pathobiological complication seen in other diseases such as diabetes, motor neuron disease and cancer, targeting mitoNEET may provide a novel mitoceutical target and therapeutic intervention for diseases that expand beyond TBI.

Original languageEnglish
Article number113243
JournalExperimental Neurology
Volume327
DOIs
StatePublished - May 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • Beam walk
  • Calcium overload
  • Controlled cortical impact
  • Mitochondrial bioenergetics
  • NL-1
  • Novel object recognition
  • Seahorse

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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