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Mitochondria in neurodegenerative disorders: regulation of the redox state and death signaling leading to neuronal death and survival

  • Basic Neurosciences, Genetics and Immunology - Review Article
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Abstract

In Parkinson’s disease, impaired function of mitochondrial complex I is involved in selective degeneration of dopamine neurons in the substantia nigra. Mitochondria are now considered to play an active role in neuronal death process through activating “intrinsic” apoptotic signaling, in addition to production of reactive oxygen species. This paper presents our recent findings on new functions of mitochondria in regulation of their redox state and function through reversible “S-glutathionylation”, a mixed disulfide binding between sulfhydryl groups of GSH and protein cysteine in complex I subunits. Type A monoamine oxidase (MAO-A) localized at the mitochondrial outer membrane is a binding site of neurotoxins leading to apoptosis. Rasagiline and (−)deprenyl, type B MAO inhibitors of propagylamine-derivatives, bind to MAO-A to protect neuronal cells against apoptosis through induction of pro-survival Bcl-2 and neurotrophic factors. This review discusses the new role of mitochondria in regulation of neuronal cell death of neurodegenerative disorders.

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Abbreviations

AIF:

Apoptosis inducing factor

ANT:

Adenine nucleotide translocator

BDNF:

Brain-derived neurotrophic factor

BKK:

Bongkrekic acid

CNTF:

Ciliary neurotrophic factor

CyP-D:

Cyclophilin-D

CsA:

Cyclosporin A

Cyt-c :

Cytochrome c

DA:

Dopamine

DAM:

Dopamine-melanin

Δψm:

Mitochondrial membrane potential

E hc :

Half-cell reduction potential

GAPDH:

Glyceraldehydes-3-phosphate dehydrogenase

GDNF:

Glial cell-line derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

GFL:

GDNF family ligand

Grx:

Glutaredoxin

GSH-Px:

Glutathione peroxidase

MAC:

Mitochondrial apoptosis-induced channel

MAO-A and MAO-B:

Type A and B monoamine oxidase

MAP:

Mitogen-activated protein

MPT:

Mitochondrial permeability transition

NGF:

Nerve growth factor

NM:

Neuromelanin

NM(R)Sal:

N-methyl(R)salsolinol

NT-3:

Neurotrophic factor-3

OX-PHOS:

Oxidative phosphorylation

PD:

Parkinson’s disease

PTP:

Permeability transition pore

SOD:

Superoxide dismutase

TSPO:

18-kDa translocator protein

Trx:

Thioredoxin

UPS:

Ubiquitin–proteasome system

VDAC:

Voltage-dependent anion channel

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Acknowledgments

This work was supported by a Grant-in-Aid for Comprehensive Research on Aging and Health from the Ministry of Health, Labor and Welfare (W. M. and M. N.), the Promotion of Fundamental Studies in Health Sciences of National Institute of Biomedical Innovation (W. M.), Japan.

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  1. Department of Neurosciences, Gifu International Institute of Biotechnology, 1-1 Nakafudogaoka, Kakamigahara, Gifu, 504-0838, Japan

    Makoto Naoi, Hong Yi, Keiko Inaba & Yukihiro Akao

  2. Department of Geriatric Medicine, National Institute for Geriatrics and Gerontology, Obu, Aichi, Japan

    Wakako Maruyama & Masayo Shamoto-Nagai

  3. United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan

    Yukihiro Akao

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  1. Makoto Naoi
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Correspondence to Makoto Naoi.

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Naoi, M., Maruyama, W., Yi, H. et al. Mitochondria in neurodegenerative disorders: regulation of the redox state and death signaling leading to neuronal death and survival. J Neural Transm 116, 1371–1381 (2009). https://doi.org/10.1007/s00702-009-0309-7

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  • DOI: https://doi.org/10.1007/s00702-009-0309-7

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