bims-humivi 2025-05-11 papers

J Evol Biol. 2025 May 05. pii: voaf042. [Epub ahead of print]

Can transcriptome size and off-target effects explain the contrasting evolution of mitochondrial vs nuclear RNA editing?

Daniel B Sloan.

Mitochondrial RNA editing has evolved independently in numerous eukaryotic lineages, where it generally restores conserved sequences and functional reading frames in mRNA transcripts derived from altered or disrupted mitochondrial protein-coding genes. In contrast to this "restorative" RNA editing in mitochondria, most editing of nuclear mRNAs introduces novel sequence variants and diversifies the proteome. This Perspective addresses the hypothesis that these completely opposite effects of mitochondrial vs. nuclear RNA editing arise from the enormous difference in gene number between the respective genomes. Because mitochondria produce a much smaller transcriptome, they likely create less opportunity for off-target editing, which has been supported by recent experimental work expressing mitochondrial RNA editing machinery in foreign contexts. In addition, there is recent evidence that the size and complexity of RNA targets may slow the kinetics and reduce efficiency of on-target RNA editing. These findings suggest that efficient targeting and a low risk of off-target editing have facilitated the repeated emergence of disrupted mitochondrial genes and associated restorative RNA editing systems via (potentially non-adaptive) evolutionary pathways that are not feasible in larger nuclear transcriptomes due to lack of precision.

Keywords: RNA editing; constructive neutral evolution; mitochondrial; target specificity; transcriptome

DOI: https://doi.org/10.1093/jeb/voaf042

Trends Mol Med. 2025 May 06. pii: S1471-4914(25)00089-9. [Epub ahead of print]

Targeting mitochondrial transfer as a promising therapeutic strategy.

Bo Li, Bingzhi Li, Xianghe Qiao, Wanrong Meng, Yuhang Xie, Jiajing Gong, Yi Fan, Zhihe Zhao, Longjiang Li.

Despite the primary impression of mitochondria as energy factories, these organelles are increasingly recognized for their multifaceted roles beyond energy production. Intriguingly, mitochondria can transfer between cells, influencing physiological and pathological processes through intercellular trafficking termed 'mitochondrial transfer.' This phenomenon is important in maintaining metabolic homeostasis, enhancing tissue regeneration, exacerbating cancer progression, and facilitating immune modulation, depending on the cell type and microenvironment. Recently, mitochondrial transfer has emerged as a promising therapeutic target for tissue repair and antitumor therapy. Here, we summarize and critically review recent advances in this field. We aim to provide an updated overview of the mechanisms and potential therapeutic avenues associated with mitochondrial transfer in various diseases from the perspective of different donor cells.

Keywords: cancer; immunity; mesenchymal stem/stromal cells MSCs; mitochondrial transfer; regeneration

DOI: https://doi.org/10.1016/j.molmed.2025.04.002

J Med Ethics. 2025 May 07. pii: jme-2024-110122. [Epub ahead of print]

Synthetic DNA and mitochondrial donation: no need for donor eggs?

Adrian Villalba, Iain Brassington, Anna Smajdor, Daniela Cutas.

Mitochondrial replacement therapy has been developed in order to prevent the transmission of mitochondrial mutations, yet it raises ethical concerns, particularly regarding the involvement of third-party DNA and the risks associated with donor procedures. This paper explores an alternative approach using synthetic DNA (synDNA) to construct mitochondrial organelles, thereby bypassing the need for donor oocytes and bypassing risks to donors. We argue that those who support mitochondrial replacement techniques as an ethically acceptable means of preventing the transmission of mitochondrial disease should consider the use of synthetic mitochondria as a preferable ethical alternative, should it prove technically viable. That this will be viable is more than we can demonstrate here. However, progress in synDNA technology suggests that it is not unreasonable to think that synthetic mitochondria creation is feasible, and perhaps even probable.

Keywords: Reproductive Medicine

DOI: https://doi.org/10.1136/jme-2024-110122

Sheng Li Xue Bao. 2025 Apr 25. 77(2): 300-308

[The regulatory effect and mechanism of PGC-1α on mitochondrial function].

Song-Hua Nan, Chao-Jie Peng, Ying-Lin Cui.

Peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) is a core member of the PGC-1 family and serves as a transcriptional coactivator, playing a crucial regulatory role in various diseases. Mitochondria, the main site of cellular energy metabolism, are essential for maintaining cell growth and function. Their function is regulated by various transcription factors and coactivators. PGC-1α regulates the biogenesis, dynamics, energy metabolism, calcium homeostasis, and autophagy processes of mitochondria by interacting with multiple nuclear transcription factors, thereby exerting significant effects on mitochondrial function. This review explores the biological functions of PGC-1α and its regulatory effects and related mechanisms on mitochondria, providing important information for our in-depth understanding of the role of PGC-1α in cellular metabolism. The potential role of PGC-1α in metabolic diseases, cardiovascular diseases, and neurodegenerative diseases was also discussed, providing a theoretical basis for the development of new treatment strategies.

DOI: https://doi.org/10.13294/j.aps.2025.0036

J Orthop Translat. 2025 May;52 220-232

Therapeutic effect of edaravone on osteoarthritis: targeting NRF2 signaling and mitochondrial function.

Chao Jiang, Yuhang Gong, Xinyu Wu, Jiangjie Chen, Yiyu Chen, Jingyao Chen, Fang Tang, Zhiyu Fang, Yuxuan Bao, Jiajing Ye, Zhangfu Wang, Zhenghua Hong.

Background: Osteoarthritis (OA), the most prevalent form of arthritis, is swiftly emerging as a chronic health condition, that poses the primary cause of disability and significant socioeconomic burden. Despite its prevalence, effective therapeutic options for OA remain elusive. This study seeks to explore the therapeutic potential of edaravone (EDA), a FDA-approved free radical scavenger, in the context of OA development and to elucidate its underlying mechanisms.
Methods: In vitro, oxidative stress models were induced by stimulating chondrocytes with t-butylhydroperoxide (TBHP); then, we investigated the influence of EDA on chondrocyte dysfunction, apoptosis, inflammatory responses and mitochondrial function in TBHP-treated chondrocytes, along with the underlying mechanisms. In vivo, destabilization of the medial meniscus (DMM) model was used to investigate the impact of EDA on OA progression. Nrf2-/- mice were applied to determine the potential role of NRF2 as a target for EDA.
Results: EDA notably alleviates chondrocyte dysfunction triggered by oxidative stress, safeguards chondrocytes from apoptosis and inflammatory responses, and preserves mitochondrial function and redox balance within chondrocytes. At the molecular level, EDA appears to halt the progression of OA by engaging and activating the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which is crucial for maintaining mitochondrial function and redox equilibrium. Notably, the protective effects of EDA on OA are abolished in Nrf2 -/- mice, underscoring the significance of the NRF2 signaling pathway in mediating EDA's therapeutic effects.
Conclusion: EDA has the potential to mitigate chondrocyte degeneration, thereby slowing the progression of OA. Thus, EDA may represent a novel therapeutic agent for the treatment of OA, potentially expanding its clinical utility.
The translational potential of this article: As a clinically licensed drug used for the treatment of neurological disorders, edaravone has shown promising therapeutic effects on OA development. Mechanistically, edaravone stabilized mitochondrial function and maintained redox homeostasis by activating NRF2 signaling pathway. The protective effects of edaravone against OA were verified in vivo and in vitro. These findings presented robust evidence for repurposing edaravone for the treatment of OA in clinic.

Keywords: Edaravone; Mitochondrial dysfunction; NRF2; Osteoarthritis; Oxidative stress

DOI: https://doi.org/10.1016/j.jot.2025.04.008