# Mechanism of ZCCHC6 Regulation of Mitochondrial Dysfunction In Alzheimer's Disease

> **NIH NIH R56** · NORTHEAST OHIO MEDICAL UNIVERSITY · 2021 · $751,425

## Abstract

PROJECT SUMMARY
Mitochondrial dysfunction is an early prominent feature in susceptible neurons in the brain of patients with
Alzheimer's disease (AD), which likely plays a critical role in the pathogenesis of AD. Mitochondria are dynamic
organelles that undergo continual fission and fusion events. Recent advances indicate that excessive
mitochondrial division (fission) is associated with functional defects and is implicated in multiple human diseases
including neurodegenerative diseases. Oxidative stress has been recognized as a contributing factor in aging
and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive
oxygen species (ROS) and disease-dependent loss of mitochondrial function are likely causally involved in loss
of hippocampal neuronal function in AD. However, molecular mechanisms underlying oxidative stress-induced
abnormal mitochondrial dynamics are yet to be determined. Mitochondrial dynamics and function may be
modulated by dysregulation of factors associated with mitochondrial fission. The major executor of fission is the
dynamin related protein 1 (DRP1), a mainly cytosolic protein which translocates to the mitochondrial surface in
order to mediate fission. Mff and Mid49/51 are mitochondrial membrane proteins that recruit DRP1 to the
mitochondria for fission. It is well established that expression of Mff and Mid49 are post-transcriptionally
regulated by specific miRNAs but it is not known why this regulation fails resulting in the increased mitochondrial
fission in AD. Importantly, our preliminary data demonstrated that in neuronal cells oxidative stress induce the
expression of ZCCHC6 which has been shown by us, and others, to uridylate miRNAs rendering them ineffective
in regulating gene expression. In our preliminary studies we also found mitochondrial network fragmentation in
N2a neurons with induced oxidative stress and that genes that regulate mitochondrial fission (Mff, Mid49) were
upregulated and miRNAs predicted to regulate their expression were downregulated. Therefore, our basic
hypothesis is that “Oxidative stress induced Zcchc6 in neurons contributes to AD pathogenesis by
rendering specific miRNAs that regulate mitochondrial fission factors ineffective by uridylation which
enhance mitochondrial fission and that inhibiting ZCCHC6 has the potential to inhibit and/or reverse
mitochondrial dysfunction in AD”. To test this hypothesis, we will characterize in detail the causal role of
aberrant ZCCHC6 expression in mediating oxidative stress-induced mitochondrial fragmentation in neurons in
vitro and the impact of in vivo depletion of Zcchc6 in two preclinical models on the development of AD and
cognitive impairment. Our findings will allow us to understand the biological and clinical relevance of oxidative
stress-induced upregulation of Zcchc6 and miRNA uridylation to regulate expression of signature genes
associated with mitochondrial impairment and fission in AD. Therefor...

## Key facts

- **NIH application ID:** 10358830
- **Project number:** 1R56AG069116-01A1
- **Recipient organization:** NORTHEAST OHIO MEDICAL UNIVERSITY
- **Principal Investigator:** Tariq M Haqqi
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $751,425
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358830

## Citation

> US National Institutes of Health, RePORTER application 10358830, Mechanism of ZCCHC6 Regulation of Mitochondrial Dysfunction In Alzheimer's Disease (1R56AG069116-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10358830. Licensed CC0.

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