# The role of FMN loss by mitochondrial Complex I in neonatal hypoxic-ischemic brain injury

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $425,704

## Abstract

In the US, perinatal hypoxia-ischemia (HI) encephalopathy brain injury remains one of the major causes of
cerebral palsy and other life-long neurological disability. The life-time cost for patients with cerebral palsy is
estimated to reach 11.5 billion dollars. This dictates a need for therapeutic strategies based on better
understanding the mechanisms of hypoxic ischemic injury. HI-reperfusion-associated oxidative stress negatively affects glycolysis, the Krebs cycle, mitochondrial
energy metabolism, and causes abnormal permeability of the inner membrane and oxidative stress. These serve
as the major factors associated with brain tissue damage in HI. However, the exact mechanisms of the so-called
secondary energy failure in ischemia/reperfusion are not known. We propose that, brain oxygen deprivation
leads to conditions in which mitochondrial complex I loses its natural cofactor, flavin mononucleotide (FMN). Our
preliminary data identifies the mechanism of flavin loss by mitochondria and show that it is taking place in the
brain in vivo and can be prevented by the administration of FMN precursor, riboflavin and hypothermia. We pursue a novel hypothesis which is consistent with experimental data observed in HI and stroke models: increased ROS generation and mitochondrial bioenergetics failure. This project investigates preclinical
approaches to attenuate this damage by modulating FMN handling. The data obtained in this study will
significantly alter the current paradigm of the origin of neuronal ischemia/reperfusion damage. We aim to prove
the major role of FMN release from mitochondria in bioenergetics failure in stroke and HI. The preclinical impact
of this project is to provide a rationale for further clinical studies aimed at the reduction of post-HI brain injury.

## Key facts

- **NIH application ID:** 9972318
- **Project number:** 1R01NS112381-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Alexander Galkin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,704
- **Award type:** 1
- **Project period:** 2020-05-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972318

## Citation

> US National Institutes of Health, RePORTER application 9972318, The role of FMN loss by mitochondrial Complex I in neonatal hypoxic-ischemic brain injury (1R01NS112381-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9972318. Licensed CC0.

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