ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease

Xinpei Gao; Zhixin Jiang; Xinfeng Yan; Jiping Liu; Fengwen Li; Peng Liu; Jialu Li; Yuehua Wei; Yi Eve Sun; Yinan Zhang; Congrong Wang

doi:10.1038/s41419-021-03993-1

ATF5, a putative therapeutic target for the mitochondrial DNA 3243A > G mutation-related disease

Cell Death Dis. 2021 Jul 14;12(7):701. doi: 10.1038/s41419-021-03993-1.

Authors

Xinpei Gao^#¹, Zhixin Jiang^#², Xinfeng Yan³, Jiping Liu¹, Fengwen Li², Peng Liu², Jialu Li¹, Yuehua Wei⁴, Yi Eve Sun⁵, Yinan Zhang⁶, Congrong Wang⁷

Affiliations

¹ Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai, China.
² Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Key Laboratory of Diabetes, Department of Endocrinology and Metabolism, Shanghai, China.
³ Shanghai East Hospital, Tongji University School of Medicine, Department of Endocrinology, Shanghai, China.
⁴ Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
⁵ Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai, China. yi.eve.sun@gmail.com.
⁶ Shanghai Jiao Tong University Affiliated Sixth People's Hospital, The Metabolic Disease Biobank, Shanghai, China. zhyn@sjtu.edu.cn.
⁷ Department of Endocrinology & Metabolism, Shanghai Fourth People's Hospital, School of Medicine, Tongji University, Shanghai, China. crwang@tongji.edu.cn.

^# Contributed equally.

Abstract

The mitochondrial DNA m.3243A > G mutation is well-known to cause a variety of clinical phenotypes, including diabetes, deafness, and osteoporosis. Here, we report isolation and expansion of urine-derived stem cells (USCs) from patients carrying the m.3243A > G mutation, which demonstrate bimodal heteroplasmy. USCs with high levels of m.3243A > G mutation displayed abnormal mitochondrial morphology and function, as well as elevated ATF5-dependent mitochondrial unfolded protein response (UPR^mt), together with reduced Wnt/β-catenin signaling and osteogenic potentials. Knockdown of ATF5 in mutant USCs suppressed UPR^mt, improved mitochondrial function, restored expression of GSK3B and WNT7B, and rescued osteogenic potentials. These results suggest that ATF5-dependent UPR^mt could be a core disease mechanism underlying mitochondrial dysfunction and osteoporosis related to the m.3243A > G mutation, and therefore could be a novel putative therapeutic target for this genetic disorder.

Publication types

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

MeSH terms

Activating Transcription Factors / genetics*
Activating Transcription Factors / metabolism
Adult
Case-Control Studies
Cell Separation
Cells, Cultured
DNA Mutational Analysis
DNA, Mitochondrial / genetics*
Female
Genetic Predisposition to Disease
Glycogen Synthase Kinase 3 beta / genetics
Glycogen Synthase Kinase 3 beta / metabolism
Heteroplasmy
Humans
Male
Mitochondria / genetics*
Mitochondria / metabolism
Mitochondria / ultrastructure
Mitochondrial Diseases / diagnosis
Mitochondrial Diseases / genetics*
Mitochondrial Diseases / urine
Mutation*
Osteogenesis
Osteoporosis / diagnosis
Osteoporosis / genetics*
Osteoporosis / urine
Phenotype
Stem Cells / metabolism*
Stem Cells / ultrastructure
Unfolded Protein Response
Urine / cytology
Wnt Proteins / genetics
Wnt Proteins / metabolism
Wnt Signaling Pathway
Young Adult

Substances

ATF5 protein, human
Activating Transcription Factors
DNA, Mitochondrial
WNT7B protein, human
Wnt Proteins
GSK3B protein, human
Glycogen Synthase Kinase 3 beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding