AUTHOR=Yang Liang , Tang Haite , Lin Xiaobing , Wu Yi , Zeng Sheng , Pan Yongzhang , Li Yukun , Xiang Ge , Lin Yi-Fang , Zhuang Shi-Mei , Song Zhiyin , Jiang Yiguo , Liu Xingguo TITLE=OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=8 YEAR=2020 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00180 DOI=10.3389/fcell.2020.00180 ISSN=2296-634X 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.