Understanding TEFM's Role in mtDNA Stability

Mitochondrial DNA (mtDNA) is crucial for cellular energy production and overall cell function. Abnormalities in mtDNA are linked to various diseases and are also believed to contribute to the aging process.

Understanding the replication and transcription processes of mtDNA is key to advancing knowledge in human health, disease, and aging. However, the precise mechanisms that regulate the balance between mtDNA transcription and replication remain unclear.

To explore these mechanisms, a research team led by Takehiro Yasukawa, Associate Professor in the Department of Molecular Pathogenesis at Juntendo University’s Graduate School of Medicine, Japan, collaborated with Dongchon Kang, Emeritus Professor at Kyushu University, and Shigeru Matsuda, Assistant Professor at Tohoku University. Their study, published in Communications Biology, investigated the role of mitochondrial transcription elongation factor (TEFM) using genome editing techniques in cultured human cells.

Although mtDNA is significantly smaller than nuclear DNA, it plays a vital role in energy production across various life forms. "During my graduate studies, I examined mitochondrial transfer RNA (tRNA) with disease-related mutations, which deepened my interest in the mechanisms of mtDNA replication and maintenance," said Dr. Takehiro Yasukawa.

The research team utilized human cells with a genome-edited TEFM knockout to assess the impact of TEFM deletion on mtDNA replication. The absence of TEFM led to a substantial decrease in mtDNA copy number, along with reductions in 7S DNA levels and strand-asynchronous replication intermediates. These findings suggest that TEFM is essential for proper mtDNA replication, particularly at the heavy strand’s origin of replication.

Additionally, the TEFM knockout resulted in an increase in transcription initiation from the light-strand promoter, indicated by elevated levels of mitochondrial tRNAPro, despite the significant decline in replication intermediates. This suggests that the loss of TEFM disrupts the balance between replication and transcription, ultimately affecting mtDNA maintenance and gene expression.

A key discovery of the study was the interaction between TEFM and DNA polymerase γ (POLG), an enzyme critical for mtDNA replication. While the study provides new insights into TEFM’s role, further research is needed to fully understand its functions. Future studies should aim to identify the precise interaction sites between TEFM and POLG on mtDNA and determine how these interactions influence replication.

"Our study addresses a fundamental question in mitochondrial gene expression regulation. It also enhances our understanding of TEFM’s role in maintaining the balance between transcription and replication, which could inform the development of treatments for diseases linked to mtDNA abnormalities," Dr. Yasukawa concluded.