LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury

Gopal V. Velmurugan, W. Brad Hubbard, Paresh Prajapati, Hemendra J. Vekaria, Samir P. Patel, Alexander G. Rabchevsky, Patrick G. Sullivan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The brain undergoes oxidative stress and mitochondrial dysfunction following physiological insults such as Traumatic brain injury (TBI), ischemia-reperfusion, and stroke. Pharmacotherapeutics targeting mitochondria (mitoceuticals) against oxidative stress include antioxidants, mild uncouplers, and enhancers of mitochondrial biogenesis, which have been shown to improve pathophysiological outcomes after TBI. However, to date, there is no effective treatment for TBI. Studies have suggested that the deletion of LDL receptor-related protein 1 (LRP1) in adult neurons or glial cells could be beneficial and promote neuronal health. In this study, we used WT and LRP1 knockout (LKO) mouse embryonic fibroblast cells to examine mitochondrial outcomes following exogenous oxidative stress. Furthermore, we developed a novel technique to measure mitochondrial morphometric dynamics using transgenic mitochondrial reporter mice mtD2g (mitochondrial-specific Dendra2 green) in a TBI model. We found that oxidative stress increased the quantity of fragmented and spherical-shaped mitochondria in the injury core of the ipsilateral cortex following TBI, whereas rod-like elongated mitochondria were seen in the corresponding contralateral cortex. Critically, LRP1 deficiency significantly decreased mitochondrial fragmentation, preserving mitochondrial function and cell growth following exogenous oxidative stress. Collectively, our results show that targeting LRP1 to improve mitochondrial function is a potential pharmacotherapeutic strategy against oxidative damage in TBI and other neurodegenerative diseases.

Original languageEnglish
Article number1445
JournalCells
Volume12
Issue number10
DOIs
StatePublished - May 2023

Bibliographical note

Publisher Copyright:
© 2023 by the authors.

Keywords

  • LDL receptor-related protein 1 (LRP1)
  • Traumatic Brain Injury (TBI)
  • mitochondria
  • mitochondrial morphology
  • mitochondrial network
  • mitostasis
  • oxidative stress

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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