Mitochondrial Unfolded Protein Response and Integrated Stress Response as Promising Therapeutic Targets for Mitochondrial Diseases

Hedong Lu; Xiaolei Wang; Min Li; Dongmei Ji; Dan Liang; Chunmei Liang; Yajing Liu; Zhiguo Zhang; Yunxia Cao; Weiwei Zou

doi:10.3390/cells12010020

Mitochondrial Unfolded Protein Response and Integrated Stress Response as Promising Therapeutic Targets for Mitochondrial Diseases

Cells. 2022 Dec 21;12(1):20. doi: 10.3390/cells12010020.

Authors

Hedong Lu^{1

2

3}, Xiaolei Wang^{1

2

3}, Min Li^{1

2

3}, Dongmei Ji^{1

4

5}, Dan Liang^{1

4

5}, Chunmei Liang^{1

4

5}, Yajing Liu^{1

4

5}, Zhiguo Zhang^{1

2

3}, Yunxia Cao^{1

2

3}, Weiwei Zou^{1

2

3}

Affiliations

¹ Reproductive Medicine Center, Department of Obstetrics and Gynecology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei 230022, China.
² NHC Key Laboratory of Study on Abnormal Gametes and Reproductive Tract, Anhui Medical University, No. 81 Meishan Road, Hefei 230032, China.
³ Key Laboratory of Population Health Across Life Cycle, Anhui Medical University, Ministry of Education of the People's Republic of China, No. 81 Meishan Road, Hefei 230032, China.
⁴ Anhui Province Key Laboratory of Reproductive Health and Genetics, No. 81 Meishan Road, Hefei 230032, China.
⁵ Biopreservation and Artificial Organs, Anhui Provincial Engineering Research Center, Anhui Medical University, No. 81 Meishan Road, Hefei 230032, China.

Abstract

The development and application of high-throughput omics technologies have enabled a more in-depth understanding of mitochondrial biosynthesis metabolism and the pathogenesis of mitochondrial diseases. In accordance with this, a host of new treatments for mitochondrial disease are emerging. As an essential pathway in maintaining mitochondrial proteostasis, the mitochondrial unfolded protein response (UPR^mt) is not only of considerable significance for mitochondrial substance metabolism but also plays a fundamental role in the development of mitochondrial diseases. Furthermore, in mammals, the integrated stress response (ISR) and UPR^mt are strongly coupled, functioning together to maintain mitochondrial function. Therefore, ISR and UPR^mt show great application prospects in the treatment of mitochondrial diseases. In this review, we provide an overview of the molecular mechanisms of ISR and UPR^mt and focus on them as potential targets for mitochondrial disease therapy.

Keywords: integrated stress response; mitochondrial diseases; mitochondrial function; mitochondrial unfolded protein response.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biological Phenomena*
Humans
Mammals
Mitochondria / metabolism
Mitochondrial Diseases* / pathology
Unfolded Protein Response

Grants and funding

This research was funded by the National Key R&D Program of China, grant number 2021YFC2700901, the National Natural Science Foundation of China, grant numbers 82001635, 81871216, 81971455 and U20A20350, the Foundation for Selected Scientists Studying Abroad of Anhui Province, grant number 2022LCX015, and Program for Outstanding Young Talents in University of Anhui, grant number gxyqZD2022027.