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

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 metabo...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179665/
https://www.ncbi.nlm.nih.gov/pubmed/32373606
http://dx.doi.org/10.3389/fcell.2020.00180
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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
author_facet 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
author_sort Yang, Liang
collection PubMed
description 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.
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spelling pubmed-71796652020-05-05 OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion 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 Front Cell Dev Biol Cell and Developmental Biology 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. Frontiers Media S.A. 2020-04-09 /pmc/articles/PMC7179665/ /pubmed/32373606 http://dx.doi.org/10.3389/fcell.2020.00180 Text en Copyright © 2020 Yang, Tang, Lin, Wu, Zeng, Pan, Li, Xiang, Lin, Zhuang, Song, Jiang and Liu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
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
OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion
title OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion
title_full OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion
title_fullStr OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion
title_full_unstemmed OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion
title_short OPA1-Exon4b Binds to mtDNA D-Loop for Transcriptional and Metabolic Modulation, Independent of Mitochondrial Fusion
title_sort opa1-exon4b binds to mtdna d-loop for transcriptional and metabolic modulation, independent of mitochondrial fusion
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179665/
https://www.ncbi.nlm.nih.gov/pubmed/32373606
http://dx.doi.org/10.3389/fcell.2020.00180
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