# The role of the mitochondrial protein dimer CHCHD2/10 in health and disease

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $425,531

## Abstract

Skeletal muscle, heart, and brain are high-energy requiring tissues that are severely affected by
mitochondrial dysfunction. Recently a novel form of genetic disease affecting mitochondria has
been associated with mutations in a mitochondrial protein, CHCHD10 (D10), whose function is
still largely unknown. Mutant D10 causes severe autosomal dominant mitochondrial diseases,
with diverse phenotypic features, ranging from myopathy to motor neuron disease and
frontotemporal dementia. We previously showed that in mitochondria D10 forms a dimeric
complex with its paralog protein, CHCHD2 (D2). Interestingly, mutations in D2 are also associated
with familial neurodegenerative diseases. To study the manifestations and disease mechanisms
of mutant D10 in vivo, we have generated a knock in mouse harboring the first pathogenic D10
mutation reported in humans (S59L, corresponding to mouse S55L). In D10S55L mouse muscle
and heart mitochondria, D10 and D2 accumulate and aggregate, leading to mitochondrial
dysfunction and degeneration. These abnormalities result in a profound integrated mitochondrial
stress response (ISRmt), altering transcriptional profiles and metabolism, and ultimately resulting
in fatal cardiomyopathy. Conversely, D10 knock out mice do not manifest mtISR and are
phenotypically normal, suggesting that D10S55L causes disease through a toxic mechanism and
not a loss of function. In this application, we will study the normal function of D10 and D2 and the
mechanisms underlying mitochondrial alterations in D10S55L mice. Since D10 mutations cause
neurodegeneration in humans, we will also investigate the involvement of the nervous system in
D10S55L mice. We will then identify metabolic and molecular biomarkers to help monitor disease
course. Lastly, we will test the effects of pharmacological modulation of ISRmt in D10S55L mice as
a therapeutic strategy. The impact of this project will be to facilitate rationale approaches to target
disease pathogenesis in patients with D10 mutations, which could be extended to other
mitochondrial diseases mediated by ISRmt

## Key facts

- **NIH application ID:** 9948765
- **Project number:** 5R01NS112672-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Giovanni Manfredi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,531
- **Award type:** 5
- **Project period:** 2019-06-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948765

## Citation

> US National Institutes of Health, RePORTER application 9948765, The role of the mitochondrial protein dimer CHCHD2/10 in health and disease (5R01NS112672-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948765. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*