OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion

Liang Yang; Haite Tang; Xiaobing Lin; Yi Wu; Sheng Zeng; Yongzhang Pan; Yukun Li; Ge Xiang; Yi-Fang Lin; Shi-Mei Zhuang; Zhiyin Song; Yiguo Jiang; Xingguo Liu

doi:10.3389/fcell.2020.00180

OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion

Front Cell Dev Biol. 2020 Apr 9:8:180. doi: 10.3389/fcell.2020.00180. eCollection 2020.

Authors

Liang Yang^{1

2}, Haite Tang^{1

2}, Xiaobing Lin^{1

2}, Yi Wu^{1

2}, Sheng Zeng³, Yongzhang Pan^{1

2}, Yukun Li^{1

2}, Ge Xiang^{1

2}, Yi-Fang Lin⁴, Shi-Mei Zhuang⁴, Zhiyin Song⁵, Yiguo Jiang⁶, Xingguo Liu^{1

2}

Affiliations

¹ CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China.
² Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Institute for Stem Cell and Regeneration, Guangzhou Institutes of Biomedicine and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Guangzhou, China.
³ State Key Laboratory of Respiratory Disease, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
⁴ MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
⁵ Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, China.
⁶ State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Abstract

Optic Atrophy 1 (OPA1) has well-established roles in both mitochondrial fusion and apoptotic crista remodeling and is required for the maintenance and distribution of mitochondrial DNA (mtDNA), which are essential for energy metabolism. However, the relationship between OPA1 and mitochondrial metabolism and the underlying mechanisms remain unclear. Here, we show that OPA1-Exon4b modulates mitochondrial respiration and rescues inner mitochondrial membrane potential (Δψm), independent of mitochondrial fusion. OPA1-Exon4b is required for the maintenance of normal TFAM distribution and enhances mtDNA transcription by binding the D-loop of mtDNA. Finally, we show that mRNA levels of OPA1 isoforms containing Exon4b are specifically downregulated in hepatocellular carcinoma (HCC), leading to a reduction in Δψm. Thus, our study demonstrates a novel mitochondrial functional self-recovery pathway involving enhanced mtDNA transcription-mediated recovery of mitochondrial respiratory chain proteins. This mitochondrial fusion-independent pathway may contribute to mitochondrial multi-functional switches in tumorigenesis.

Keywords: Optic Atrophy 1 (OPA1); hepatocellular carcinoma; mitochondrial DNA; mitochondrial fusion; mtDNA D-loop.