# Reprogramming proinflammatory microglia by restoring mitochondrial function

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $603,383

## Abstract

Traumatic brain injury (TBI) is a major source of long-term disability and dementia. Microglia, long-lived
immune cells of the brain, activate to multiple reactive states in response to injury. The extent of pro-inflammatory
activation correlates with the severity of neurological impairments, suggesting that unresolved activation is
pathogenic. The proposed research is highly significant because it will evaluate a clinically safe intervention to
ameliorate harmful TBI-induced microglial activation that may contribute to dementia and other chronic
neurological deficits following TBI. Our data suggest that a metabolic shift from oxidative phosphorylation to
glycolysis during pro-inflammatory activation involves impairment to the lysosomal turnover of damaged
mitochondria by mitophagy, which is followed by Complex I subunit degradation. Idebenone restores oxygen
consumption by damaged mitochondria and attenuates pro-inflammatory nitric oxide and interleukin-1beta
production. The restoration of oxygen consumption by idebenone decreases intracellular oxygen concentration.
We found that simply lowering oxygen concentration by incubating cells under hypoxia prevents Complex I
degradation and mitophagy impairment. Unexpectedly, antioxidants failed to yield similar rescue, suggesting a
role for oxygen that is independent of oxidative stress. Using proteomics, we discovered a marked accumulation
of prolyl 3-hydroxylase 2 (P3H2) in a mitochondria/lysosome-enriched cell fraction. P3H2 gene expression within
the brain is microglia-specific, and our preliminary data show elevated P3H2 in mouse peri-contusional cortex
after TBI. P3H2 enzyme uses oxygen as a substrate for proline hydroxylation of target proteins. Idebenone may
suppress the activity of P3H2 by decreasing oxygen availability, preventing P3H2 from post-translationally
modifying mitochondria or lysosome proteins involved in quality control. This study will test the central
hypothesis that idebenone suppresses TBI-induced microglial activation, chronic neurodegeneration, and
cognitive deficits by reversing P3H2-dependent inhibition of mitophagy. The following specific aims employ state-of-the-art mouse models to monitor microglial mitochondrial turnover and include novel methods to sort and
study microglia ex vivo based on mitochondrial function. The experiments in Aim 1 will test the prediction that
idebenone rescues mitophagy in pro-inflammatory microglial cells by decreasing intracellular oxygen
concentration, thereby inhibiting P3H2 activity. Using both male and female mice and considering sex as a
variable, the experiments in Aim 2 will test the prediction that idebenone or genetic P3H2 knockout ameliorates
TBI-induced pro-inflammatory microglia accumulation and neurological deficits by rescuing microglial mitophagy.
Positive outcomes will support translational studies of idebenone to treat TBI-induced dementia, with the
potential to help millions of men and women living with the devastating con...

## Key facts

- **NIH application ID:** 10201784
- **Project number:** 5R01NS112212-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** BRIAN M POLSTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $603,383
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201784

## Citation

> US National Institutes of Health, RePORTER application 10201784, Reprogramming proinflammatory microglia by restoring mitochondrial function (5R01NS112212-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201784. Licensed CC0.

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