bims-mitran 2026-09-27 papers

Issue of 2026–09–27
three papers selected by
Andreas Kohler, Umeå University

bioRxiv. 2026 Jun 25. pii: 2026.06.23.733767. [Epub ahead of print]

ATAD3A structurally links mtDNA replication and mitochondrial fission.

Nitish Dua, Boyuan Ma, Samantha Oviedo, Hamidreza Rahmani, Tumara Boyd, Donghyun Park, R Luke Wiseman, Danielle A Grotjahn.

Mitochondrial function depends on the maintenance of its genome, and disruptions in copy number and distribution are hallmarks of mitochondrial disorders. Mitochondrial DNA (mtDNA) replication is spatially and temporally linked to mitochondrial division (i.e., fission). However, the signal that coordinates these two events, which are physically separated by the barrier of two mitochondrial membranes, remains unknown. To gain insight into this coordination, we employed correlative cryo-electron tomography (cryo-ET) to analyze the microenvironment surrounding replicating nucleoids. Mitochondrial regions containing replicating mtDNA exhibit a unique membrane architecture defined by the presence of clustered, membrane-spanning tethers that traverse the inner membrane space. Using a combination of superresolution microscopy and genetically encoded cryo-ET tagging technology, we identify these tethers as the AAA+ ATPase ATAD3A. We further show that ATAD3A knockdown reduces recruitment of the mitochondrial fission machinery, whereas overexpression promotes its recruitment and subsequent fission. Our work suggests that ATAD3A forms nanoscale linkages that coordinate these two distinct processes, revealing a new structural paradigm for organellar communication across distinct membrane-defined environments.
Highlights: Replicating mitochondrial DNA (mtDNA) nucleoids are surrounded by a distinct membrane microenvironment.ATAD3A forms membrane-spanning tethers enriched at replicating mtDNA sites.ATAD3A enrichment is necessary and sufficient to recruit mitochondrial fission machinery and induce fission at mtDNA replication sites.ATAD3A structurally couples mtDNA replication state to mitochondrial fission across distinct organellar subcompartments.

DOI: https://doi.org/10.64898/2026.06.23.733767

PLoS Biol. 2026 Sep 21. 24(9): e3003945

The kinetoplastid-specific transcription factor mtTF1 is essential for mitochondrial gene expression and maxicircle replication in Trypanosoma brucei.

Bianca Manuela Berger, Enrico Santini, Himaja Manjunatha, Lea Trost, Markus Gerber, Hauke S Hillen, Torsten Ochsenreiter.

Mitochondrial DNA replication and gene expression are essential for cell survival. In Trypanosoma brucei, a protozoan animal and human parasite, the mitochondrial RNA polymerase (mtRNAP, Tb927.11.5780) plays roles in both transcription and DNA replication. This study identifies and characterizes the first mitochondrial transcription factor (mtTF1, Tb927.6.4510) in the Kinetoplastea. The mtRNAP and mtTF1 form a high-molecular-weight complex that localizes to the kinetoplast DNA (kDNA) and is essential for parasite survival in both life cycle stages. Their localization is interdependent, and both proteins influence maxicircle replication, but not minicircle replication. Knockdown of either protein results in altered gene expression, particularly affecting the minor strand of the mitochondrial genome. mTF1 specifically binds to kDNA and since it is unique to the Kinetoplastea, it might prove to be a promising drug target.

DOI: https://doi.org/10.1371/journal.pbio.3003945

Nucleic Acids Res. 2026 Sep 22. pii: gkag925. [Epub ahead of print]54(18):

Molecular and structural basis for replication initiation and strand separation by human mitochondrial DNA polymerase γ.

Viktoriia Sokolova, Gina Buchel, Sarah Strock, Ashok R Nayak, Dmitry Temiakov.

Defects in human mitochondrial DNA (mtDNA) replication can lead to somatic mutations associated with a range of devastating mitochondrial diseases. However, the molecular mechanisms governing the earliest steps of mtDNA replication and their fidelity remain poorly understood. Here, we found that DNA polymerase gamma (Polγ) forms stable complexes with RNA-DNA primer-template substrates, exhibiting greater stability and lower misincorporation than on DNA-primed substrates. Structural analysis revealed that Polγ interacts with the 2'-OH groups of ribose within the first four nucleotides of the primer, explaining the stability of complexes that utilize RNA primers. Although Polγ requires TWINKLE to extend RNA primers, its intrinsic strand-displacement activity allows it to extend DNA primers independently. Structural data further show that the strand-separation mechanism in human Polγ is distinct from that of its yeast paralog, Mip1, and involves previously unresolved elements-the catcher and a GP loop in the exonuclease domain-that support intrinsic strand-displacement synthesis by Polγ. Structure-guided mutagenesis of elements involved in strand separation supports these structural observations. Together, our study provides mechanistic insight into mtDNA replication initiation and strand separation and has implications for understanding the molecular basis of mitochondrial disease.

DOI: https://doi.org/10.1093/nar/gkag925