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

Author:

Velmurugan Gopal V.12,Hubbard W. Brad134ORCID,Prajapati Paresh123ORCID,Vekaria Hemendra J.123ORCID,Patel Samir P.14,Rabchevsky Alexander G.14,Sullivan Patrick G.123ORCID

Affiliation:

1. Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY 405036, USA

2. Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA

3. Lexington Veterans’ Affairs Healthcare System, Lexington, KY 40502, USA

4. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA

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.

Funder

VA Merit

National Institutes of Health National Institute of Neurological Disorders and Stroke

Kentucky Spinal Cord and Head Injury Research Trust

Publisher

MDPI AG

Subject

General Medicine

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