The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain DOI Creative Commons

Jule Gerlach,

Paola Pireddu,

Xiaoqun Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 14, 2024

Abstract The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations genes have been linked to severe disorders, including Parkinson’s disease amyotrophic lateral sclerosis. In cultured cells, a fraction of oligomerize form high molecular weight complex unknown function. Here, we generated whole-body Chchd2 knockout mouse investigate vivo role its protein complex. We show that is crucial for sustaining full motor capacity, normal striatal dopamine levels, lipid homeostasis brain adult male mice. also demonstrate tissues, exist exclusively as complex, whose levels finely tuned under physiological conditions. response dysfunction, abundance size CHCHD2-CHCHD10 increases, mechanism across different tissues. Although loss does not abolish oligomerization, it enhances cell vulnerability stress, suggesting protective against damage. Our findings uncover preserving tissue provide important insights into involvement human diseases.

Language: Английский

CHCHD2 P14L, found in amyotrophic lateral sclerosis, exhibits cytoplasmic mislocalization and alters Ca2+ homeostasis DOI Creative Commons

Aya Ikeda,

Hongrui Meng, Daisuke Taniguchi

et al.

PNAS Nexus, Journal Year: 2024, Volume and Issue: 3(8)

Published: July 30, 2024

CHCHD2 and CHCHD10, linked to Parkinson's disease amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed investigate the impact of P14L variant, implicated in ALS, on function its subsequent effects cellular homeostasis. The missense variant CHCHD2, P14L, found cohort patients with mislocalized cytoplasm, leaving CHCHD10 mitochondria.

Language: Английский

Citations

1
Establishment of a novel amyotrophic lateral sclerosis patient (TARDBPN345K/+)-derived brain microvascular endothelial cell model reveals defective Wnt/β-catenin signaling: investigating diffusion barrier dysfunction and immune cell interaction DOI Creative Commons
Kinya Matsuo,

Jun Nagamatsu,

Kazuhiro Nagata

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: Aug. 15, 2024

Amyotrophic lateral sclerosis (ALS) is a major neurodegenerative disease for which there currently no curative treatment. The blood-brain barrier (BBB), multiple physiological functions formed by mainly specialized brain microvascular endothelial cells (BMECs), serves as gatekeeper to protect the central nervous system (CNS) from harmful molecules in blood and aberrant immune cell infiltration. accumulation of evidence indicating that alterations peripheral milieu can contribute neurodegeneration within CNS suggests BBB may be previously overlooked factor pathogenesis ALS. Animal models suggest breakdown precede link alteration progression or even onset. However, lack useful patient-derived model hampers understanding pathomechanisms dysfunction development BBB-targeted therapies. In this study, we differentiated BMEC-like human induced pluripotent stem (hiPSCs) derived ALS patients investigate BMEC patients.

Language: Английский

Citations

1
The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain DOI Creative Commons

Jule Gerlach,

Paola Pireddu,

Xiaoqun Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 14, 2024

Abstract The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations genes have been linked to severe disorders, including Parkinson’s disease amyotrophic lateral sclerosis. In cultured cells, a fraction of oligomerize form high molecular weight complex unknown function. Here, we generated whole-body Chchd2 knockout mouse investigate vivo role its protein complex. We show that is crucial for sustaining full motor capacity, normal striatal dopamine levels, lipid homeostasis brain adult male mice. also demonstrate tissues, exist exclusively as complex, whose levels finely tuned under physiological conditions. response dysfunction, abundance size CHCHD2-CHCHD10 increases, mechanism across different tissues. Although loss does not abolish oligomerization, it enhances cell vulnerability stress, suggesting protective against damage. Our findings uncover preserving tissue provide important insights into involvement human diseases.

Language: Английский

Citations

0