# Mitokines as new targets for fatigue induced by mitochondrial stress

> **NIH NIH R21** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $445,500

## Abstract

Project Summary/Abstract
Fatigue is one of the most common and disruptive symptoms experienced by patients. It is present in about one
out of five individuals in the general population, and its prevalence increases dramatically, up to and above 50%,
in several medical conditions such as cancer and viral infections. The specific mechanisms responsible for fatigue
remain largely unknown. Consequently, there are no mechanism-guided therapies for this condition. Although
inflammation is often presented as a primary cause of fatigue, it is not always present in many instances of
chronic fatigue. An alternative mechanism is mitochondrial dysfunction, as attested by the pivotal role of
mitochondria in energy metabolism and the sensitivity of these organelles to cellular stress caused by toxins and
pathogens. While it is not surprising that fatigue is the hallmark of mitochondrial diseases, what is still missing
is how the deficit in energy metabolism caused by mitochondrial stress in metabolically active peripheral organs
is transmitted to the brain to give rise to the feeling of fatigue and its behavioral expression. Mitokines such as
GDF15 and FGF21 are candidates for such a communication as they are produced as both paracrine and
hormonal factors to maintain energy homeostasis in conditions of mitochondrial stress. To test our hypothesis
that mitokines induce fatigue by acting in the brain we will assess the ability of exogenously administered GDF15
and FGF21 to induce fatigue and study their receptor mechanisms (Aim 1) before determining whether their
release as endogenous factors in response to mitochondrial stress mediates the fatigue that develops in this
condition (Aim 2). In both aims, we will measure fatigue and its motivational component (the “can” and “will”
aspects of fatigue) by decreased voluntary activity and reduced ability to engage in effortful behavior to obtain a
reward. The tools used to study the role of GDF15 include a long-acting form of GDF15 and a neutralizing
monoclonal antibody targeting its receptor, GFRAL. In addition, we will use chemogenetic approaches targeting
CCK or TH contained in GFRAL expressing neurons in the hindbrain to identify its central site of action. The
tools used to study the role of FGF21 include an analog of FGF21, LY2405319 administered via subcutaneously
implanted osmotic minipumps, and a peptide antagonist of -klotho, the obligatory co-receptor of FGF21
receptors, that will be administered peripherally or centrally. Mitochondrial stress will be induced by
administration of cisplatin, a cytotoxic agent used in chemotherapy, tunicamycin, a toxic compound that induces
the unfolded protein response, and lipopolysaccharide. They all induce the release of both GDF15 and FGF21.
The importance of mitochondrial stress will be checked by comparing wild type mice to Tfam+/- mice that have
mitochondrial instability and should be more sensitive to the fatigue inducing effects of cisplatin. This preclinical
proj...

## Key facts

- **NIH application ID:** 10598758
- **Project number:** 1R21NS130712-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Robert Dantzer
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $445,500
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598758

## Citation

> US National Institutes of Health, RePORTER application 10598758, Mitokines as new targets for fatigue induced by mitochondrial stress (1R21NS130712-01). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10598758. Licensed CC0.

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