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Molecular Neurobiology

, Volume 54, Issue 7, pp 5534–5546 | Cite as

Mitochondrial CHCHD-Containing Proteins: Physiologic Functions and Link with Neurodegenerative Diseases

  • Zhi-Dong Zhou
  • Wuan-Ting Saw
  • Eng-King Tan
Article

Abstract

The coiled-coil-helix-coiled-coil-helix domain (CHCHD)-containing proteins are evolutionarily conserved nucleus-encoded small mitochondrial proteins with important functions. So far, nine members have been identified in this protein family. All CHCHD proteins have at least one functional coiled-coil-helix-coiled-coil-helix (CHCH) domain, which is stabilized by two pairs of disulfide bonds between two helices. CHCHD proteins have various important pathophysiological roles in mitochondria and other key cellular processes. Mutations of CHCHD proteins have been associated with various human neurodegenerative diseases. Mutations of CHCHD10 are associated with amyotrophic lateral sclerosis (ALS) and/or frontotemporal lobe dementia (FTD), motor neuron disease, and late-onset spinal muscular atrophy and autosomal dominant mitochondrial myopathy. CHCHD10 stabilizes mitochondrial crista ultrastructure and maintains its integrity. In patients with CHCHD10 mutations, there are abnormal mitochondrial crista structure, deficiencies of respiratory chain complexes, impaired mitochondrial respiration, and multiple mitochondrial DNA (mtDNA) deletions. Recently, CHCHD2 mutations are linked with autosomal dominant and sporadic Parkinson’s disease (PD). The CHCHD2 is a multifunctional protein and plays roles in regulation of mitochondrial metabolism, synthesis of respiratory chain components, and modulation of cell apoptosis. With a better understanding of the pathophysiologic roles of CHCHD proteins, they may be potential novel therapeutic targets for human neurodegenerative diseases.

Keywords

Apoptosis Coiled-coil-helix-coiled-coil-helix domain proteins Mitochondria Mitochondrial cristae Neurodegenerative disease 

Abbreviations

ALS

Amyotrophic lateral sclerosis

AD

Alzheimer’s disease

CHCH

Coiled-coil-helix-coiled-coil-helix

CHCHD

Coiled-coil-helix-coiled-coil-helix domain

COX

Cytochrome c oxidase

CPC

Cysteine-proline-cysteine motif

DA

Dopamine

EGFR

Epidermal growth factor receptor

FTD

Frontotemporal lobe dementia

GBA

Guilt-by-association analysis

HPA

Human Protein Atlas project

IMM

The mitochondrial inner membrane

IMMD

The autosomal dominant mitochondrial myopathy

IMS

The mitochondrial intermembrane space

ISE

The mitochondrial iron-sulfur exporter machinery

ITS

The mitochondrial IMS-targeting signal

MICOS

The mitochondrial contact site complex

MOMP

The mitochondrial OMM permeabilization

mtDNA

Mitochondrial DNA

MTS

The mitochondrial targeting sequence

NSCLC

Non-small-cell lung carcinoma

OMM

The mitochondrial outer membrane

ORE

Oxygen-responsive element

OxPhos

The oxidative phosphorylation process

PD

Parkinson’s disease

RBPJ

The recombination signal sequence-binding protein Jκ

ROS

Redox oxygen species

SMAJ

The late-onset spinal muscular atrophy, Jokela type

tBID

The truncated form of BID

WT

Wild type

Notes

Acknowledgments

We thank Singapore National Medical Research Council (STaR and Transition awards and clinical translational research programme in Parkinson’s disease) for their support.

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

Funding

This study is supported by Singapore National Medical Research Council (NMRC) grants including STaR and Transition awards and clinical translational research programme in Parkinson’s disease.

Supplementary material

12035_2016_99_MOESM1_ESM.docx (16 kb)
Supplementary Table 1 Predicted MTS fragment in CHCHD proteins (DOCX 15 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.National Neuroscience Institute of SingaporeSingaporeSingapore
  2. 2.Signature Research Program in Neuroscience and Behavioural DisordersDuke-NUS Graduate Medical School SingaporeSingaporeSingapore
  3. 3.Department of NeurologySingapore General HospitalSingaporeSingapore

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