# Molecular Mechanisms and Functions of Mitochondrial Ca2+ transport in Neurons

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $315,892

## Abstract

Mitochondria play a central role in cell metabolism and control multiple aspects of neuronal signaling. By
efficiently buffering Ca2+ influx during neuronal excitation and slowly releasing Ca2+ back into the cytosol,
mitochondria shape [Ca2+]i transients and regulate Ca2+-dependent neuronal functions, such as excitability,
synaptic transmission and gene expression. Ca2+ rise in the mitochondrial matrix stimulates Ca2+-dependent
dehydrogenases and boosts ATP production to meet the increase in energy demand during excitation.
However, mitochondrial overload with Ca2+ can kill neurons, and mitochondrial Ca2+ dysregulation is implicated
in neuronal damage during stroke and in neurodegenerative disorders, such as Alzheimer's and Parkinson's
diseases. Despite the importance of mitochondrial Ca2+ transport to neuronal life and death, the molecules that
mediate mitochondrial Ca2+ uptake and release in neurons are not known. This knowledge gap presents a
major obstacle in our progress toward understanding and therapeutically correcting mitochondrial functions in
neurons. The main objectives of this proposal are to identify molecules that mediate mitochondrial Ca2+ uptake
in peripheral and central neurons, and to establish their roles in neuronal Ca2+ signaling, ATP synthesis,
synaptic transmission and excitotoxicity. Our preliminary studies indicate that two novel molecules, MCU
(CCDC109A) and MCUb (CCDC109B), are broadly expressed in the peripheral and central nervous systems,
and that MCU is required for mitochondrial Ca2+ uptake in neurons whereas MCUb inhibits this Ca2+ transport
mechanism. Moreover, our pilot data using MCU KO mice showed that MCU loss dramatically, but not
completely, reduced mitochondrial Ca2+ uptake, altered Ca2+ signaling and mitochondrial function and provided
remarkable protection against glutamate-induced toxicity. Our central hypothesis is that MCU and MCUb play
important but opposite roles in the regulation of mitochondrial Ca2+ uptake in neurons, bioenergetics, Ca2+
signaling and synaptic transmission, and that knockout of MCU, but not of MCUb, protects neurons from
excitotoxicity and reduces neuronal damage in ischemic stroke. We will employ a multidisciplinary approach
involving genetic Ca2+ and ATP sensors, patch-clamp recording, knockout mice and a mouse model of
ischemic stroke to test this hypothesis in three specific aims. Aim 1 will establish the roles of MCU and MCUb
in mitochondrial Ca2+ transport and Ca2+ signaling in central and peripheral neurons. Aim 2 will examine the
impact of MCU and MCUb on presynaptic Ca2+ signaling and synaptic transmission. Aim 3 will establish the
roles of MCU and MCUb in excitotoxicity and ischemic stroke. We anticipate that this work will be
transformative because it will establish the molecular basis for genetic and pharmacological manipulation of
mitochondrial Ca2+ transport in neurons, and may lead to the development of new therapeutics that target
mitochondrial Ca2+ uniporters fo...

## Key facts

- **NIH application ID:** 9996358
- **Project number:** 5R01NS096246-05
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Yuriy M Usachev
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $315,892
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996358

## Citation

> US National Institutes of Health, RePORTER application 9996358, Molecular Mechanisms and Functions of Mitochondrial Ca2+ transport in Neurons (5R01NS096246-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9996358. Licensed CC0.

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