# Mitochondrial Energy Sensing and Neuronal Ischemia

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $396,385

## Abstract

Neuronal survival or death depends strongly on mitochondrial function and metabolic signaling following
stroke. Ischemic stroke causes changes in mitochondrial function that, depending on severity or persistence,
can result in either damage or protection. However, the mechanisms that regulate the balance between these
outcomes are not fully understood, but likely depend on how, when and where mitochondrial function changes.
As mitochondrial function and signaling are dependent on the mitochondrial membrane potential (Δψm), our
central hypothesis is that neuronal ischemic outcomes depend on the timing and degree of Δψm
(de)polarization. Currently, the field lacks tools to assess the contribution of Δψm to ischemic outcomes
independent of other variables. Our proposal addresses this gap by applying a novel optogenetic approach to
regulate the Δψm, thereby dissociating it from upstream metabolism. Conventional optogenetic approaches use
light-sensitive proteins to control neuronal plasma membrane potentials. Here we will apply this approach in
mitochondria to either increase or decrease the Δψm in response to different wavelengths of light. We will use a
novel CRISPR/Cas9 method to express our light-activated proteins at single-copy levels to take unprecedented
spatial and temporal control of bioenergetics in vivo. This system can mimic or reverse the Δψm changes that
occur during stroke. Combined with the power of C. elegans genetics and epistasis, this approach will probe
the molecular mechanisms that mediate mitochondrial signaling in hypoxic pathology. Using neuron-selective
gene expression, we will test how mitochondrial function affects ischemic outcomes in different types of
neurons. In addition, we will characterize how bioenergetics influences the neuronal circuits that signal during
ischemic pathology. Overall, the results of our approach will allow us to integrate the contribution of Δψm, an
elusive, dependent variable, to stress outcomes in order to better guide future therapeutic strategies.

## Key facts

- **NIH application ID:** 9939131
- **Project number:** 1R01NS115906-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Andrew Phillip Wojtovich
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,385
- **Award type:** 1
- **Project period:** 2020-02-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939131

## Citation

> US National Institutes of Health, RePORTER application 9939131, Mitochondrial Energy Sensing and Neuronal Ischemia (1R01NS115906-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939131. Licensed CC0.

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