# Regulation of Mitochondrial Gene Expression and Function by GDF11 Signaling

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $448,750

## Abstract

Dysfunction in cellular energy homeostasis is a defining feature of Alzheimer disease (AD) and related
dementias. Importantly, the expression of most mitochondrial genes is downregulated in the brain of patients
with AD but the mechanisms responsible for these AD-associated transcriptional changes are largely unknown.
Moreover, many studies indicate that mitochondria from AD patients differ structurally and functionally from those
of control individuals. On the basis of these findings, improving mitochondrial gene expression and function has
been proposed as a therapy to block or delay the progression of AD. However, no such therapy is available.
 In R01-funded research, we are investigating the role of the myokine (a muscle-secreted factor) Myoglianin,
the Drosophila homolog of human GDF11. As in humans, mitochondrial dysfunction is a prevalent feature of
tissue aging in Drosophila. We find that Myoglianin promotes mitochondrial gene expression and maintains
mitochondrial function during skeletal muscle aging via the transcription factor vismay/TGIF (TGFb-induced
factor). Interestingly, its human homolog TGIF1 has been recently identified as a key neuroprotective master
regulator of transcriptional changes in AD pathogenesis, based on the analysis of transcriptome and proteome
data from brains of neuropathologically-confirmed AD patients compared to age-matched non-demented
controls.
 On this basis, we propose to expand our R01-funded studies to explore the relevance of GDF11/TGIF
signaling for brain aging and AD-like conditions in Drosophila. Specifically, we propose to test whether GDF11
receptor/TGIF signaling contrasts the decline in mitochondrial gene expression and function that occurs in the
brain during aging and in an AD-like condition (pathogenic tau overexpression). Considering that TGIF1 has
been recently implicated in AD and that GDF11 has been already involved in brain rejuvenation via undefined
mechanisms, our studies promise to provide mechanistic understanding on how GDF11/TGIF signaling
preserves brain function during aging.
 In summary, these studies propose to test in Drosophila the role of GDF11/TGIF signaling in modulating
mitochondrial gene expression and function during brain aging and in AD-like conditions. Knowledge gained
from these studies will provide fundamental understanding of the interconnection of mitochondrial dysfunction
with AD, and explore the efficacy of GDF11/TGIF-based interventions for this pathogenic component of AD.

## Key facts

- **NIH application ID:** 10123309
- **Project number:** 3R01AG055532-04S1
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Fabio Demontis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $448,750
- **Award type:** 3
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123309

## Citation

> US National Institutes of Health, RePORTER application 10123309, Regulation of Mitochondrial Gene Expression and Function by GDF11 Signaling (3R01AG055532-04S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10123309. Licensed CC0.

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