# Mitochondrial complex-I as a target for metabolic resuscitation in perinatal hypoxic-ischemic brain injury

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $394,870

## Abstract

SUMMARY
 A worldwide mortality from perinatal hypoxic-ischemic insult reaches 1.2 million annually. In the US,
perinatal HI-brain injury remains one of the major causes of cerebral palsy (CP) and life-long neurological
disability. The life-time cost for patients with CP was estimated to reach 11.5 billion dollars. This dictates a
need for therapeutic strategies based on better understanding the mechanisms of HI injury. We propose that,
upon reperfusion, inhibition of complex-I recovery with novel compound, MitoSNO, protects developing brain
against HI injury. MitoSNO is mitochondria-targeted agent that maintains C-I in the de-active form (D) via S-
nitrosation of Cys-39 residue. Because, the reactivation of the C-I supports a reverse-electron transport
mechanism of ROS production, the proposed mechanism of neuroprotection is attenuation of the reperfusion-
initiated oxidative stress and protection of the D-form from irreversible oxidation of thiols. Aim 1 determines a
contribution of succinate-dependent mitochondrial respiration to accelerated ROS generation and to
bioenergetics recovery initiated by the reperfusion. Mechanistically, this aim provides the rationale for inhibition
of complex-I recovery to block reverse electron transport, the mechanism for ROS generation burst in
reperfusion. Aim 1 and 2 determines whether transient inhibition of C-I recovery with MitoSNO attenuates
mitochondrial oxidative damage and preserves mitochondrial tolerance to Ca++ induced development of mPTP,
and whether this limits the severity of secondary energy failure. Aim 2 addresses specificity of MitoSNO
neuroprotective action to the S-nitrosation the Cys39 in the D-form of the C-I. Aim 2 also evaluates long-term
neuroprotective effects of the MitoSNO. This project offers a strong mechanistic background for the
development of clinically relevant and novel therapeutic strategy of metabolic resuscitation in which gradual
metabolic recovery is the mainstream principle.

## Key facts

- **NIH application ID:** 9893935
- **Project number:** 5R01NS100850-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Vadim S Ten
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,870
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893935

## Citation

> US National Institutes of Health, RePORTER application 9893935, Mitochondrial complex-I as a target for metabolic resuscitation in perinatal hypoxic-ischemic brain injury (5R01NS100850-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9893935. Licensed CC0.

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