bims-mitran 2024-12-01 papers

Issue of 2024–12–01
three papers selected by
Andreas Kohler, Umeå University

Genome Res. 2024 Nov 27. pii: gr.279072.124. [Epub ahead of print]

Chimeric mitochondrial RNA transcripts predict mitochondrial genome deletion mutations in mitochondrial genetic diseases and aging.

Amy R Vandiver, Allen Herbst, Paul Stothard, Jonathan Wanagat.

While it is well understood that mitochondrial DNA (mtDNA) deletion mutations cause incurable diseases and contribute to aging, little is known about the transcriptional products that arise from these DNA structural variants. We hypothesized that mitochondrial genomes containing deletion mutations express chimeric mitochondrial RNAs. To test this, we analyzed human and rat RNA sequencing data to identify, quantitate, and characterize chimeric mitochondrial RNAs. We observed increased chimeric mitochondrial RNA frequency in samples from patients with mitochondrial genetic diseases and in samples from aged humans. The spectrum of chimeric mitochondrial transcripts reflected the known pattern of mtDNA deletion mutations. To test the hypothesis that mtDNA deletions induce chimeric RNA transcripts, we treated 18 mo and 34 mo rats with guanidinopropionic acid to induce high levels of skeletal muscle mtDNA deletion mutations. With mtDNA deletion induction, we demonstrate that the chimeric mitochondrial transcript frequency also increased and correlated strongly with an orthogonal DNA-based mutation assay performed on identical samples. Further, we show that the frequency of chimeric mitochondrial transcripts predicts expression of both nuclear and mitochondrial genes central to mitochondrial function, demonstrating the utility of these events as metrics of age-induced metabolic change. Mapping and quantitation of chimeric mitochondrial RNAs provides an accessible, orthogonal approach to DNA-based mutation assays, offers a potential method for identifying mitochondrial pathology in widely accessible datasets, and opens a new area of study in mitochondrial genetics and transcriptomics.

DOI: https://doi.org/10.1101/gr.279072.124

Nat Chem Biol. 2024 Nov 28.

Mitochondria-localized MBD2c facilitates mtDNA transcription and drug resistance.

Yijie Hao, Zilong Zhou, Rui Liu, Shengqi Shen, Haiying Liu, Yingli Zhou, Yuchen Sun, Qiankun Mao, Tong Zhang, Shi-Ting Li, Zhaoji Liu, Yiyang Chu, Linchong Sun, Ping Gao, Huafeng Zhang.

Mitochondria contain a 16-kb double stranded DNA genome encoding 13 proteins essential for respiration, but the mechanisms regulating transcription and their potential role in cancer remain elusive. Although methyl-CpG-binding domain (MBD) proteins are essential for nuclear transcription, their role in mitochondrial DNA (mtDNA) transcription is unknown. Here we report that the MBD2c splicing variant translocates into mitochondria to mediate mtDNA transcription and increase mitochondrial respiration in triple-negative breast cancer (TNBC) cells. In particular, MBD2c binds the noncoding region in mtDNA and interacts with SIRT3, which in turn deacetylates and activates TFAM, a primary mitochondrial transcription factor, leading to enhanced mtDNA transcription. Furthermore, MBD2c recovered the decreased mitochondrial gene expression caused by the DNA synthesis inhibitor cisplatin, preserving mitochondrial respiration and consequently enhancing drug resistance and proliferation in TNBC cells. These data collectively demonstrate that MBD2c positively regulates mtDNA transcription, thus connecting epigenetic regulation by deacetylation with cancer cell metabolism, suggesting druggable targets to overcome resistance.

DOI: https://doi.org/10.1038/s41589-024-01776-1

Redox Biol. 2024 Nov 21. pii: S2213-2317(24)00414-2. [Epub ahead of print]78 103436

Human mitochondrial peroxiredoxin Prdx3 is dually localized in the intermembrane space and matrix subcompartments.

Fernando Gomes, Helena Turano, Luciana A Haddad, Luis E S Netto.

Peroxiredoxin 3 (Prdx3) is the major sink for H2O2 and other hydroperoxides within mitochondria, yet the mechanisms guiding the import of its cytosolic precursor into mitochondrial sub-compartments remain elusive. Prdx3 is synthesized in the cytosol as a precursor with an N-terminal cleavable presequence, which is frequently proposed to target the protein exclusively to the mitochondrial matrix. Here, we present a comprehensive analysis of the human Prdx3 biogenesis, using highly purified mitochondria from HEK293T cells. Subfractionation and probing for specific mitochondrial markers confirmed Prdx3 localization in the matrix, while unexpectedly revealed its presence in the mitochondrial intermembrane space (IMS). Both matrix and IMS isoforms were found to be soluble proteins, as demonstrated by alkaline carbonate extraction. By combining in silico analysis, in organello import assays and heterologous expression in yeast, we found that Prdx3 undergoes sequential proteolytic processing steps by mitochondrial processing peptidase (MPP) and mitochondrial intermediate peptidase (MIP) during its import into the matrix. Additionally, heterologous expression of Prdx3 in yeast revealed that its sorting to the IMS is dependent on the inner membrane peptidase (IMP) complex. Collectively, these findings uncover a complex submitochondrial distribution of Prdx3, supporting its multifaceted role in mitochondrial H2O2 metabolism.

Keywords: Intermembrane space (IMS); Matrix; Mitochondria; Peroxiredoxin; Prdx3

DOI: https://doi.org/10.1016/j.redox.2024.103436