# Non-invasive mitochondrial modulation therapy for ischemic stroke

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $446,582

## Abstract

Summary:
Ischemic stroke is a leading cause of death and long-term disability in the US. The current gold
standard for the treatment of ischemia-reperfusion injury in the setting of focal brain ischemia is
restoration of blood flow with recanalization. However, a substantial portion of the damage
caused by ischemia/reperfusion occurs during the reperfusion phase: as ischemic tissue is
reoxygenated, reactive oxygen species (ROS) are quickly generated, starting early during reflow.
Reperfusion injury has proved difficult to treat pharmacologically, likely because effective drug
concentrations have not built up sufficiently during the early phase of reperfusion.
The mitochondrial electron transport chain (ETC) is a major site of ROS production during cellular
stress due to ETC hyper-activation, which causes high mitochondrial membrane potentials (∆Ψm),
which in turn trigger excessive ROS production. We propose that the ideal therapy should target
the ETC non-invasively to prevent the generation of ROS from the onset of reflow. Accordingly,
our overall goal in this application is to develop a new, non-invasive therapy to normalize
mitochondrial hyperactivity during reflow. We will capitalize on the photoreceptive
properties of cytochrome c oxidase (COX) for near infrared light (NIR) to modulate
mitochondrial activity, thereby attenuating the production of ROS and, as a result, limit
ischemia/reperfusion injury in the brain. Cytochrome c oxidase is the primary cellular photo-
acceptor of NIR and the terminal enzyme of the ETC. We have discovered specific NIR
wavelengths that partially inhibit COX (instead of activating COX, i.e., the current paradigm).
We show that inhibitory NIR, applied at the time of reperfusion, provides profound
neuroprotection. In this proposal, we will build on these compelling preliminary data and
capitalize on the unique, multi-disciplinary expertise of our research team to:
 • Interrogate the molecular underpinnings of ischemia/reperfusion injury and of NIR therapy
 (Aim 1).
 • Uncover the mechanisms of NIR therapy following stroke (Aim 2)
 • Develop the optimal use of NIR therapy as a treatment for ischemic stroke (Aim 3).

## Key facts

- **NIH application ID:** 10816508
- **Project number:** 5R01NS120322-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MAIK HUETTEMANN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $446,582
- **Award type:** 5
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816508

## Citation

> US National Institutes of Health, RePORTER application 10816508, Non-invasive mitochondrial modulation therapy for ischemic stroke (5R01NS120322-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10816508. Licensed CC0.

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