Mitochondrial deoxyribonucleic acid (mtDNA) is essential for cellular energy production and overall cell function. Abnormalities in mtDNA are linked to various diseases and are also implicated in aging. Understanding the process of replication and transcription of mtDNA is crucial for improving our knowledge of human health, disease, and aging. However, the mechanisms that regulate the balance between transcription and replication of mtDNA remain unclear.
To unveil the mechanisms, a team of researchers led by Takehiro Yasukawa, an Associate Professor from Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Japan, along with Dongchon Kang, an Emeritus Professor of Kyushu University, Japan, and Shigeru Matsuda, an Assistant Professor from Tohoku University, Japan, investigated the role of mitochondrial transcription elongation factor (TEFM) by utilizing genome editing techniques in cultured human cells. Their study was published in the journal, Communications Biology , on February 08, 2025.
"While mtDNA is much smaller than nuclear DNA, it plays a crucial role in life forms through energy production. During my graduate studies, I investigated mitochondrial transfer ribonucleic acids (RNAs) with disease-related mutations, which further intrigued me to explore the mechanism of mtDNA replication and maintenance in real depth," says Dr. Yasukawa.
Using cultured human cells with genome-edited TEFM knockout, the team studied the effects of deletion of TEFM on mtDNA replication. By knocking out TEFM, they observed a notable reduction in mtDNA copy number, alongside a decrease in 7S DNA levels and strand-asynchronous replication intermediates. These findings suggest that TEFM is crucial for the proper regulation of mtDNA replication, particularly at the origin of replication of the heavy strand.
In addition, the deletion of TEFM resulted in an increase in transcription initiation from the light-strand promoter, as suggested by higher levels of mitochondrial tRNAPro, but replication intermediates were still significantly reduced. This suggests that the absence of TEFM disrupts the proper balance between the replication and transcription processes, which has consequences on mtDNA maintenance and expression. Another significant finding of this study was the interaction between TEFM and the DNA polymerase γ (POLG), an essential enzyme involved in mtDNA replication.
Despite the significant progress made in understanding the role of TEFM in mtDNA replication, further research is needed to fully unravel the detailed mechanisms behind its action. Future studies are required to identify the exact locations of TEFM and POLG interaction on mtDNA and how they influence the entire replication process.
"Our study addresses one of the fundamental questions of gene expression regulation in mitochondria. In addition, it deepens our understanding of the role of TEFM in maintaining the balance between transcription and replication of mtDNA, potentially paving the way for the development of treatment strategies for diseases that result from abnormalities in mtDNA," concludes Dr. Yasukawa.
Reference
Authors |
Shigeru Matsuda1,2, Masunari Nakayama1, YuraDo1, Takashi Ishiuchi3,4, Mikako Yagi1,5, Sjoerd Wanrooij6, KazutoNakada7, Fan-Yan Wei 2, Kenji Ichiyanagi8, Hiroyuki Sasaki3, Dongchon Kang1,10, and Takehiro Yasukawa1,9 |
Title of original paper |
TEFM facilitates transition from RNA synthesis to DNA synthesis at H-strand replication origin of mtDNA |
Journal |
Communications Biology |
DOI |
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Affiliations |
1Department of Clinical Chemistry and Laboratory Medicine, Kyushu University, Japan 2Department of Modomics Biology and Medicine, Tohoku University, Japan 3Division of Epigenomics and Development, Kyushu University, Japan 4Faculty of Life and Environmental Sciences, University of Yamanashi, Japan 5Department of Health Sciences, Kyushu University, Japan. 6Department of Medical Biochemistry and Biophysics, Umeå University, Sweden 7Institute of Life and Environmental Sciences, University of Tsukuba, Japan 8Department of Animal Sciences, Nagoya University, Japan 9Department of Molecular Pathogenesis, Juntendo University Graduate School of Medicine, Japan |
About Associate Professor Takehiro Yasukawa
Dr. Takehiro Yasukawa is an Associate Professor at Department of Molecular Pathogenesis, Graduate School of Medicine, Juntendo University, Japan, specializing in mitochondrial biology. Dr. Yasukawa has made significant contributions to the understanding of mitochondrial DNA replication and mitochondrial disease. With years of dedicated research, he continues to explore the complexities of mitochondrial mechanisms, aiming to uncover potential treatments for mitochondrial disease and aging. In addition, he has expanded his research into cancer biology and focuses on the complexity of tumor microenvironment.
