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Review
. 2018 Oct 1;61(3):R91-R105.
doi: 10.1530/JME-18-0005.

The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases

Hyon-Seung Yi  1 , Joon Young Chang  1   2 , Minho Shong  1
Affiliations
Review

The mitochondrial unfolded protein response and mitohormesis: a perspective on metabolic diseases

Hyon-Seung Yi et al. J Mol Endocrinol. .

Abstract

Mitochondria perform essential roles as crucial organelles for cellular and systemic energy homeostasis, and as signaling hubs, which coordinate nuclear transcriptional responses to the intra- and extra-cellular environment. Complex human diseases, including diabetes, obesity, fatty liver disease and aging-related degenerative diseases are associated with alterations in mitochondrial oxidative phosphorylation (OxPhos) function. However, a recent series of studies in animal models have revealed that an integrated response to tolerable mitochondrial stress appears to render cells less susceptible to subsequent aging processes and metabolic stresses, which is a key feature of mitohormesis. The mitochondrial unfolded protein response (UPRmt) is a central part of the mitohormetic response and is a retrograde signaling pathway, which utilizes the mitochondria-to-nucleus communication network. Our understanding of the UPRmt has contributed to elucidating the role of mitochondria in metabolic adaptation and lifespan regulation. In this review, we discuss and integrate recent data from the literature on the present status of mitochondrial OxPhos function in the development of metabolic diseases, relying on evidence from human and other animal studies, which points to alterations in mitochondrial function as a key factor in the regulation of metabolic diseases and conclude with a discussion on the specific roles of UPRmt and mitohormesis as a novel therapeutic strategy for the treatment of obesity and insulin resistance.

Keywords: mitochondria; oxidative phosphorylation; mitochondrial unfolded protein response; diabetes; insulin resistance.

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Conflict of interest statement

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Figures

Figure 1
Figure 1
Scientific interests in mitochondria from 1950 to 2016. The articles were identified in PubMed using the term ‘mitochondria’ for each year from 1950 to 2016. The articles were expressed as the total number of mitochondria articles out of all articles, as well as mitochondria articles as a percentage of all articles in PubMed. The essential milestones and discoveries in the field of mitochondrial research are described by the year of publication.
Figure 2
Figure 2
Total number and percentage of ‘Mitochondria,’ ‘Oxidative phosphorylation,’ ‘UPRmt’ and ‘Metabolic disease’ articles in PubMed from 1950 to 2016.
Figure 3
Figure 3
Mitochondrial chaperones and proteases. Schematic cartoon describes the major factors involved in mitochondrial proteostasis. The chaperones and proteases are located in mitochondrial outer and inner membrane, intermembrane space and matrix.
Figure 4
Figure 4
Schematic model regarding the importance of mitokine response in progression of metabolic diseases.
See this image and copyright information in PMC

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