# Mechanism of age-dependent neuromuscular degeneration caused by protein misfolding on the inner mitochondrial membrane

> **NIH NIH F30** · UPSTATE MEDICAL UNIVERSITY · 2020 · $50,520

## Abstract

PROJECT SUMMARY
Mitochondria are essential organelles responsible for many cellular processes including energy production
through oxidative phosphorylation (OXPHOS), calcium signaling, redox homeostasis, and cell death. Many of
these functions are executed by a densely packed network of proteins in the inner mitochondrial membrane
(IMM). As such, mitochondrial functions depend on protein homeostasis (proteostasis) in the IMM. IMM
proteostasis is maintained by an extensive protein quality control system composed, in part, of IMM proteases
that degrade misfolded proteins. Persistent IMM protein misfolding is speculated to cause a growing number of
age-dependent neurodegenerative and neuromuscular degenerative diseases. For example, mutations in IMM
proteases cause Parkinson's disease, spinocerebellar ataxia, spastic ataxia syndrome, spastic paraplegia, and
other neurodegenerative diseases. Does a failure to degrade misfolded IMM proteins cause these diseases?
This is unknown. In addition, misfolded variants of the ADP/ATP exchanger in the IMM, Ant1, cause
autosomal dominant Progressive External Ophthalmoplegia and a mitochondrial myopathy. We used one such
misfolded Ant1 variant to dissect the cellular consequences of IMM protein misfolding in yeast. Unexpectedly,
IMM protein misfolding does not kill yeast cells by affecting essential mitochondrial functions in the IMM, but
instead by disrupting mitochondrial protein import causing the toxic accumulation of mitochondrial precursor
proteins in the cytosol. This novel mechanism was termed mitochondrial precursor overaccumulation stress
(mPOS). It is not known if mPOS occurs in higher organisms, or if it can contribute to disease. Moreover,
despite the significant clinical implications, the physiological consequences of IMM protein misfolding are
poorly understood. To address these issues, we generated a novel knock-in (KI) mouse model expressing a
pathogenic misfolded variant of Ant1. A fraction of KI mice undergo drastic neurodegeneration culminating in
paralysis, thus confirming the pathogenic potential of IMM protein misfolding and providing a tool for in vivo
mechanistic studies. Non-paralyzed KI mice exhibit exercise intolerance and reduced skeletal muscle
mitochondrial respiration in skeletal muscle. This raises the possibility that IMM protein misfolding causes
damage to specific components in the OXPHOS pathway leading to muscle weakness. We test this
hypothesis in Aim 1. In addition to OXPHOS deficiency, cytosolic protein degradation pathways are activated in
skeletal muscle of “asymptomatic” KI mice. The activation of cytosolic protein degradation pathways suggests
that cytosolic proteostasis is challenged, possibly via mPOS. Therefore, in Aim 2, we test the hypothesis that
IMM protein misfolding induces mPOS in KI mouse muscle to cause muscle weakness. The mechanism(s)
revealed in this proposal will be important for understanding the role of IMM protein misfolding in Ant1-induced
pathologi...

## Key facts

- **NIH application ID:** 9980255
- **Project number:** 5F30AG060702-03
- **Recipient organization:** UPSTATE MEDICAL UNIVERSITY
- **Principal Investigator:** Liam Patrick Coyne
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-08-30 → 2022-08-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980255

## Citation

> US National Institutes of Health, RePORTER application 9980255, Mechanism of age-dependent neuromuscular degeneration caused by protein misfolding on the inner mitochondrial membrane (5F30AG060702-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980255. Licensed CC0.

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