# The Pathogenic Mechanism of C19orf12 in Mitochondrial  Membrane Protein Associated Neurodegeneration

> **NIH NIH R03** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $80,500

## Abstract

Abstract
Neurodegeneration in brain with iron accumulation (NBIA) defines a group of rare hereditary diseases with
prominent features of iron deposition and related neuronal loss in the nervous system. Although significant
progress in the genetic studies uncovered the essential role of mitochondrial dysfunction in the pathogenesis
of NBIA, the underlying mechanism of mitochondrial abnormality and metal dysregulation in NBIA remains
elusive. In this regard, we focused on the mitochondrial membrane proteins associated iron accumulation
(MPAN) that was caused by genetic mutations in C19orf12, a protein with unknown function. In the pilot
study, we analyzed human biopsy of an MPAN case, mouse brain tissue and human neuroblastoma M17 cell
lines with C19orf12 knock-out (KO) to explore the role of C19orf12 in the mitochondria of MPAN and also in
the normal mitochondria. Indeed, our preliminary data of imaging investigation on brain biopsy of MPAN
conditions suggested mitochondria are impaired in the surviving neurons, which underscored the
mitochondrial dysfunction in MPAN. The exploration of C19orf12 in vivo showed the mitochondrial
localization and protein expression of C19orf12 in mouse brain tissues. Importantly, we found that C19orf12 is
associated with mitochondrial complex IV of the electron transfer chain in vivo. In vitro study of C19orf12,
mitochondrial respiration analysis of C19orf12 KO M17 cells showed impaired mitochondrial oxygen
consumption in vitro. Furthermore, trace metal analysis showed both iron and copper dysregulation in the
mitochondria of C19orf12 KO cells. Taken together, this exciting data demonstrated that the critical role of
C19orf12 in mitochondrial function and metal regulation in the physiological condition and the likely related
disturbance of C19orf12 during the pathogenesis of MPAN. Therefore, the further study to explore the
mechanism of metal regulation in MPAN and how C19orf12 mutants impair mitochondrial function is
warranted. The current application will shed light on the novel mechanism of C19orf12 that is linking
mitochondrial dysfunction and metal dysregulation in the MPAN pathology.

## Key facts

- **NIH application ID:** 9977289
- **Project number:** 5R03NS112782-02
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Wenzhang Wang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $80,500
- **Award type:** 5
- **Project period:** 2019-07-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977289

## Citation

> US National Institutes of Health, RePORTER application 9977289, The Pathogenic Mechanism of C19orf12 in Mitochondrial  Membrane Protein Associated Neurodegeneration (5R03NS112782-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9977289. Licensed CC0.

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