# Alterations in somatodendritic bioenergetics in Drosophila models of tauopathy

> **NIH NIH RF1** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2021 · $1,159,932

## Abstract

Ionic homeostasis in the somatodendritic compartment of neurons is maintained by pumps that utilize the energy
of ATP hydrolysis to set the resting membrane potential and prevent toxic elevations in cytosolic [Ca2+]. The
relative contributions of glycolysis and mitochondrial respiration in meeting the ATP burden associated with the
activity of these pumps is poorly understood. Also unclear is how these two axes of ATP production are perturbed
in neurodegenerative disease such as Alzheimer’s and related dementias (ADRDs), which exhibit bioenergetic
deficits and ionic dyshomeostasis. In this proposal, we detail our plans to elucidate the relative contributions of
glycolysis and mitochondrial ATP synthesis to the somatodendritic ATP burden stemming with depolarization
and the release of Ca2+ from the endoplasmic reticulum (ER). By imaging of cytosolic/mitochondrial [Ca2+] and
[ATP]/[ADP] ratio in live dissociated Drosophila neurons we have formulated the model that ATP burden of
depolarization is so tightly coupled to ATP synthesis such that somatodendritic [ATP]/[ADP] ratio remained stable
in depolarized neurons. Our preliminary data also suggest that depolarization elicits ATP production in the
somatodendritic compartment without a necessity for concomitant changes in mitochondrial [Ca2+]. Given that in
the absence of matrix [Ca2+] elevations mitochondrial ATP production is not potentiated, we hypothesize that
glycolysis, rather than OXPHOS, is the favored bioenergetic response to depolarization. We will test this
hypothesis in aim 1, and also determine whether the Na+/K+ ATPase and plasma membrane Ca2+ ATPase
(PMCA) are the recipients of glycolysis-derived ATP in depolarized neurons. Aim 2 is driven by our preliminary
finding that ER Ca2+ release via inositol trisphosphate receptors (IP3Rs) in depolarized neurons desynchronized
ATP production from consumption. We will also probe the significance of Ca2+ transfer between the ER and
mitochondria, and attendant changes in neuronal bioenergetics in a fly model of tauopathies, which stem from
our preliminary findings show that expression of a toxic human Tau variant in fly glutamatergic neurons disrupted
Ca2+ transfer between ER and mitochondria, and evoked toxicity that was consistent with Ca2+ dyshomeostasis.
In summary, we will use a range of imaging tools and direct measures of bioenergetics to address fundamental
questions of metabolic regulation in neurons, and interrogate the mechanism by which these parameters are
perturbed in a model of ADRD.

## Key facts

- **NIH application ID:** 10199400
- **Project number:** 1RF1AG072176-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** KARTIK VENKATACHALAM
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,159,932
- **Award type:** 1
- **Project period:** 2021-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199400

## Citation

> US National Institutes of Health, RePORTER application 10199400, Alterations in somatodendritic bioenergetics in Drosophila models of tauopathy (1RF1AG072176-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10199400. Licensed CC0.

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