# Mitochondrial mechanisms and signaling in manganese exposure

> **NIH NIH R01** · EMORY UNIVERSITY · 2024 · $355,878

## Abstract

Summary:
This application focuses on a novel pathogenic mechanism that includes metal homeostasis,
mitochondrial proteostasis and onset of neurological adverse effects for cognition and movement. We
have identified the mitochondrial RNA granule, as a key initiator of neuronal responses to environmental
and/or genetic insults that predispose an individual to disease. This RNA processing pathway in
mitochondria resides upstream of the effects that have been attributed to manganese toxicity, including
reduced respiratory chain activity, mitochondrial membrane depolarization, mitochondrial oxidative
stress, leading to cell death. Our overall hypothesis is that manganese accumulation in mitochondria
disrupts the mitochondrial RNA granule function and induces dsRNA accumulation as part of the toxicity
mechanism. This disruption leads to the accumulation of dsRNA and reduced OXPHOS function and
increased oxidative stress. Thus, the mitochondrial RNA granule offers us a molecular reporter of
exposure and sensitivity to manganese and a potential target for neuroprotective interventions.
Specific Aims:
Aim 1: Identify molecular targets of manganese in mitochondria.
Aim 2: Evaluate whether manganese-induced mitochondrial dysfunction induces dsRNA accumulation
and pro-inflammatory responses.
Aim 3: To test to what degree impaired mitochondrial RNA granule function modulates manganese sensitivity
in human brain organoids and brain from wild type and SLC30a10 KO mouse.
Study Design: We will employ cell models with genetic deficiencies in the manganese efflux
transporter SLC30A10, which is sufficient to induce a parkinsonian syndrome in humans, as well as
acutely and chronically manganese treated cells to identify Manganese binding proteins in mitochondria
and to analyze the composition of the mitochondrial RNA granule by mass spectrometry approaches.
RNA granule function will be studied by analyzing the processing of the mitochondrial polycistronic
mitochondrial RNA in manganese challenged cells employing molecular counting with probes directed
at unprocessed junctions in the transcripts. By knockout and over-expression of RNA granule
components, we will assess whether mitochondrial RNA granule dysfunction is deleterious or adaptive.
We will interrogate human brain organoids and mouse brain tissue for the molecular mechanisms
identified in cell line models. Given the significant potential impact of RNA granule on mitochondrial
function, we will evaluate whether drugs affecting mitochondrial RNA processing and downstream
metabolism are neuroprotective to excess manganese exposure or exacerbate genetic vulnerability.

## Key facts

- **NIH application ID:** 10907826
- **Project number:** 5R01ES034796-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** AVANTI GOKHALE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $355,878
- **Award type:** 5
- **Project period:** 2023-08-16 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907826

## Citation

> US National Institutes of Health, RePORTER application 10907826, Mitochondrial mechanisms and signaling in manganese exposure (5R01ES034796-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10907826. Licensed CC0.

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