# Mitochondrial free radical production, biogenesis and their effect on liver regeneration after Acetaminophen (APAP) overdose.

> **NIH NIH F31** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2020 · $33,236

## Abstract

Project Summary/Abstract
 Acetaminophen (APAP) is a safe analgesic and antipyretic drug commonly used as a pain reliever
and fever reducer. However, intentional or accidental APAP overdose leads to hepatocyte cell death and is the
major cause of acute liver failure (ALF) in the U.S. The measurement of blood biomarkers of mitochondrial
damage draws a parallel in the clinic with unfavorable outcome in overdose patients. Moreover, recent findings
on the protective effect of agents that promote mitochondrial glutathione recovery and mitochondrial
superoxide dismutase action reveal that mitochondrial oxidant stress (reactive oxygen species, ROS) and
peroxynitrite (RNS) formation and ATP depletion are fundamental steps in the pathophysiology of APAP
induced liver injury in mice and humans. The only approved clinical therapy to remedy this APAP-induced
mitochondrial toxicity is the administration of N-acetyl cysteine (NAC). NAC is very effective at preventing
mitochondrial damage when given early. Unfortunately, NAC therapy fails the majority of overdose patients
because they seek medical attention too late. Interestingly, our preliminary data indicate that delayed
interventions that scavenge ROS may actually delay regeneration and recovery. Thus, there is a critical need
for a delayed targeted therapy that will benefit late presenting APAP overdose patients. Disruption of
mitochondrial dynamics is a common feature of mitochondrial oxidant stress and the role of Mitochondrial
Biogenesis (MB) in accelerating recovery and regeneration after injury has been reported in various organs.
Also, mitochondria ROS/RNS has been shown to maintain cellular homeostasis by inducing MB as a
compensatory mechanism. However, the role of MB in influencing regeneration after APAP overdose has not
yet been studied. Thus, the goal of this proposal is to determine whether induction of MB would be a better
strategy for promoting hepatocytes regeneration and liver recovery after APAP-mediated liver injury. Based on
our preliminary data we developed the hypothesis, that APAP-induced mitochondrial oxidant stress has
dual roles with higher levels, during the early injury phase, inducing hepatocyte necrosis and lower
levels, at later times, activating the adaptive MB response. Therefore, further investigation of the benefit of
MB induction as well as the effect of NAC on MB is necessary and will be the focus of this proposal. To
achieve this goal, 3 aims will be investigated. The first aim will examine MB effect on liver regeneration after
APAP overdose. The second aim will study the function of ROS/RNS production in relation with MB induction.
The third aim will explore the role of MB and its outcome on recovery after APAP hepatotoxicity in models of
human relevance such as HepaRG cells. This proposal has major health and clinical implications. It will clearly
help clarify the role of MB in the liver in influencing clinical outcome after APAP overdose. It will also provide a
clear...

## Key facts

- **NIH application ID:** 9997931
- **Project number:** 5F31DK120194-03
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Jephte Y. Akakpo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $33,236
- **Award type:** 5
- **Project period:** 2018-09-09 → 2021-09-08

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9997931

## Citation

> US National Institutes of Health, RePORTER application 9997931, Mitochondrial free radical production, biogenesis and their effect on liver regeneration after Acetaminophen (APAP) overdose. (5F31DK120194-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9997931. Licensed CC0.

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