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Review
. 2017 Sep 16;24(1):74.
doi: 10.1186/s12929-017-0380-6.

Roles of sigma-1 Receptors on Mitochondrial Functions Relevant to Neurodegenerative Diseases

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Free PMC article
Review

Roles of sigma-1 Receptors on Mitochondrial Functions Relevant to Neurodegenerative Diseases

Tzu-Yu Weng et al. J Biomed Sci. .
Free PMC article

Abstract

The sigma-1 receptor (Sig-1R) is a chaperone that resides mainly at the mitochondrion-associated endoplasmic reticulum (ER) membrane (called the MAMs) and acts as a dynamic pluripotent modulator in living systems. At the MAM, the Sig-1R is known to play a role in regulating the Ca2+ signaling between ER and mitochondria and in maintaining the structural integrity of the MAM. The MAM serves as bridges between ER and mitochondria regulating multiple functions such as Ca2+ transfer, energy exchange, lipid synthesis and transports, and protein folding that are pivotal to cell survival and defense. Recently, emerging evidences indicate that the MAM is critical in maintaining neuronal homeostasis. Thus, given the specific localization of the Sig-1R at the MAM, we highlight and propose that the direct or indirect regulations of the Sig-1R on mitochondrial functions may relate to neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). In addition, the promising use of Sig-1R ligands to rescue mitochondrial dysfunction-induced neurodegeneration is addressed.

Keywords: Mitochondria; Mitochondrion-associated ER membrane (MAM); Neurodegenerative disorders; Sigma-1 receptor.

Conflict of interest statement

Authors’ information

Tzu-Yu Weng (tyweng@gate.sinica.edu.tw), postdoc fellow, Academia Sinica, Taiwan. Shang-Yi Anne Tsai (stsai@nih.gov), Scientific Review Officer, NIDA Division of Extramural Research, and Tsung-Ping Su (TSU@intra.nida.nih.gov), Chief, Cellular Pathobiology Section, Integrative Neuroscience Branch, Intramural Research Program, NIDA, NIH, Baltimore, Maryland.

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors have read the manuscript and agreed to the publication.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
The putative model of Sig-1R at the MAM. a In the normal state, the Sig-1R interacts with BiP. Upon agonist stimulation or the decline of ER Ca2+, the Sig-1R dissociates from BiP to stabilize the IP3R3 for Ca2+ signaling from ER into mitochondria and to regulate the IRE1-dependent pathway to counteract the ER stress. The Sig-1R protects against apoptosis and ROS via the Bcl-2- or Nrf2-dependent pathways. Sig-1Rs can also associate with VDAC2 or Rac1. b The depletion of Sig-1R leads to an abnormal Ca2+ signaling between ER and mitochondria and the disruption of the ATP production. Enhanced ROS production, increased cytochrome c release, or reduced Bcl-2 can cause ER stress that leads to the collapse of the MAM and consequently enhanced autophagy or apoptotic cell death

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