bims-midysc Biomed News
on Mitochondria dysfunction in cancer
Issue of 2025–04–06
two papers selected by
Papachristodoulou Lab, NJ State University at Rutgers
  1. Retromer promotes the lysosomal turnover of mtDNA.
  2. An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.
  1. Sci Adv. 2025 Apr 04. 11(14): eadr6415
    Retromer promotes the lysosomal turnover of mtDNA.
    Parisa Kakanj, Mari Bonse, Arya Kshirsagar, Aylin Gökmen, Felix Gaedke, Ayesha Sen, Belén Mollá, Elisabeth Vogelsang, Astrid Schauss, Andreas Wodarz, David Pla-Martín.
      Mitochondrial DNA (mtDNA) is exposed to multiple insults produced by normal cellular function. Upon mtDNA replication stress, the mitochondrial genome transfers to endosomes for degradation. Using proximity biotinylation, we found that mtDNA stress leads to the rewiring of the mitochondrial proximity proteome, increasing mitochondria's association with lysosomal and vesicle-related proteins. Among these, the retromer complex, particularly VPS35, plays a pivotal role by extracting mitochondrial components. The retromer promotes the formation of mitochondrial-derived vesicles shuttled to lysosomes. The mtDNA, however, directly shuttles to a recycling organelle in a BAX-dependent manner. Moreover, using a Drosophila model carrying a long deletion on the mtDNA (ΔmtDNA), we found that ΔmtDNA activates a specific transcriptome profile to counteract mitochondrial damage. Here, Vps35 expression restores mtDNA homoplasmy and alleviates associated defects. Hence, we demonstrate the existence of a previously unknown quality control mechanism for the mitochondrial matrix and the essential role of lysosomes in mtDNA turnover to relieve mtDNA damage.
    DOI:  https://doi.org/10.1126/sciadv.adr6415
  2. Mol Ther. 2025 Apr 03. pii: S1525-0016(25)00260-6. [Epub ahead of print]
    An engineered mitoCBE facilitates efficient mitochondrial DNA editing and modified mitochondrial transfer.
    Jie Liu, Jun Chen, Shisheng Huang, Junfan Guo, Xiangyang Li, Ying Yan, Ruijing Chen, Guanglei Li, Ming Liu, Jiao Wei, Xingxu Huang, Yunbo Qiao.
      Double-stranded DNA (dsDNA) cytosine deaminase DddA orthologs from multiple types of bacteria have been fused with TALE system for mitochondrial DNA (mtDNA) base editing, while the efficiencies remain limited and its nuclear off-targeting activity cannot be ignored yet. Here we identified a DddA ortholog from Burkholderia gladioli (BgDddA) and generated nuclear or mitochondrial DNA cytosine base editors (mitoCBEs), exhibiting higher C•G-to-T•A editing frequencies compared to canonical DdCBE, and fusion with transactivator Rta remarkably improved editing efficiencies by up to 6.4-fold at non-TC targets. Referring to DddA11, we further introduced six substitutions into BgDddA and generated mitoCBE3.2, which efficiently induced disease-associated mtDNA mutations in mouse and human cell lines at both TC and non-TC targets with efficiency reaching up to 99.2%. Using mitoCBE3.2, single clones containing homoplasmic mtDNA mutations or premature stop codons associated with human diseases were generated, and the functions of these mutations have been evaluated upon the treatment of ROS inducers. Importantly, mitochondria harboring these homoplasmic mutations were transplanted into wildtype cells, enabling precise base conversions, without risk of nuclear gene off-targets. Thus, we have engineered an efficient mitoCBE using BgDddA, facilitating mitochondrial disease modeling and potential mutation correction with the aid of mitochondrial transplantation.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.03.051
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒28 at 16:35.