# Modulation of intermediate metabolism, a new therapeutic approach for mitochondrial encephalomyopathies

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $466,125

## Abstract

Project Summary
Mitochondrial diseases are heterogeneous genetic disorders caused by the impairment of the
oxidative phosphorylation (OXPHOS) system, affecting tissues that are heavily energy
dependent, and often manifesting with neuromuscular symptoms accompanied by a variety of
additional clinical features. Although the energetic defects arising from genetic errors in
mitochondrial and nuclear DNA are often known, many aspects of mitochondrial disease
pathogenesis are yet to be elucidated. As a consequence, because of the lack of defined
metabolic targets, no proven effective treatments or cures are available. Our published studies
indicate that a dramatic metabolic remodeling occurs in vivo in a mouse model of mitochondrial
disease. We found that a starvation-like response promotes muscle protein breakdown and amino
acid catabolism to support a compensatory energy-generating oxidative flux. In this flux,
glutamate is oxidized through the TCA cycle and allows for OXPHOS-independent substrate-level
ADP phosphorylation. At the same time, lipid utilization through -oxidation is downregulated and
therefore this maladaptive process results in muscle wasting and lipid accumulation. Importantly,
in preliminary studies leading to this application, we have discovered that skeletal muscle from
mitochondrial patients affected by Myoclonus Epilepsy and Ragged Red Fibers (MERRF)
encephalomyopathy show similar compensatory metabolic responses. We also find that the
hypothalamic–pituitary–adrenal axis is altered leading to increased glucocorticoid levels, which
can play a role in muscle protein and lipid dyshomeostasis. Our findings suggest that this
metabolic shift towards preferred utilization of amino acids over lipids for energetic purposes
underlies maladaptive effects, contributing to disease pathogenesis. In aim 1 of this pilot study,
we will provide proof of principle that metabolic rewiring caused by OXPHOS defects are common
features in animal models and human patients with mitochondrial diseases. We will also test the
hypothesis that energy substrate supplementation can provide beneficial metabolic modulation in
patient-derived muscle cells. Furthermore, in aim 2, we will test an innovative metabolic therapy
in a mouse model of mitochondrial disease by glucocorticoid signal inhibition with or without
metabolic supplementation with dimethyl-alpha ketoglutarate.

## Key facts

- **NIH application ID:** 10218518
- **Project number:** 1R21NS118233-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Qiuying Chen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $466,125
- **Award type:** 1
- **Project period:** 2021-05-01 → 2023-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218518

## Citation

> US National Institutes of Health, RePORTER application 10218518, Modulation of intermediate metabolism, a new therapeutic approach for mitochondrial encephalomyopathies (1R21NS118233-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10218518. Licensed CC0.

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