bims-mitran 2023-04-30 papers

Issue of 2023–04–30
four papers selected by
Andreas Kohler, University of Graz

Autophagy. 2023 Apr 28.

Autophagy Inhibition as a Potential Therapeutic Strategy for Breast Cancer with Mitochondrial Translation Defect Caused by CBFB-Deficiency.

Navdeep Malik, Hualong Yan, Young-Im Kim, Gamze Ayaz, Shasha Wang, Payel Mondal, Ji Luo, Jing Huang.

Autophagy plays a crucial role in tumor initiation and progression. However, targeting autophagy in cancer has proven challenging due to genetic or epigenetic factors that may affect the efficacy of autophagy inhibition. Therefore, identifying biomarkers is crucial for selecting patients who are likely to benefit from this treatment modality. We show that dysregulation of mitochondrial translation caused by CBFB (core-binding factor subunit beta) deficiency can sensitize the tumors to autophagy inhibition. CBFB and its binding partner HNRNPK (heterogeneous nuclear ribonucleoprotein K) interact with mRNAs encoded by the mitochondrial genome (mt-mRNAs) and maintain their translation. Specifically, CBFB enhances the binding of TUFM (Tu translation elongation factor, mitochondrial), an elongation factor for mitochondrial translation, to mt-mRNAs. CBFB deficiency, which often occurs in estrogen receptor-positive breast tumors, results in elevated autophagy and mitophagy that promote cancer cell survival. Consequently, these cells are hypersensitive to autophagy inhibition, creating a targetable vulnerability. Studies using in vivo models have shown that inhibiting autophagy selectively eliminates breast tumor cells with mitochondrial translation defects resulting from CBFB deficiency. Our results suggest that autophagy inhibition may be an effective treatment option for breast tumors carrying CBFB alterations.

Keywords: Autophagy; CBFB; PIK3CA; autophagy in cancer; autophagy targeting; breast cancer; mitochondria; mitochondrial translation; mitophagy

DOI: https://doi.org/10.1080/15548627.2023.2208481

J Fungi (Basel). 2023 Apr 05. pii: 445. [Epub ahead of print]9(4):

A Correlation between 3'-UTR of OXA1 Gene and Yeast Mitochondrial Translation.

Maryam Hajikarimlou, Mohsen Hooshyar, Noor Sunba, Nazila Nazemof, Mohamed Taha Moutaoufik, Sadhena Phanse, Kamaledin B Said, Mohan Babu, Martin Holcik, Bahram Samanfar, Myron Smith, Ashkan Golshani.

Mitochondria possess their own DNA (mtDNA) and are capable of carrying out their transcription and translation. Although protein synthesis can take place in mitochondria, the majority of the proteins in mitochondria have nuclear origin. 3' and 5' untranslated regions of mRNAs (3'-UTR and 5'-UTR, respectively) are thought to play key roles in directing and regulating the activity of mitochondria mRNAs. Here we investigate the association between the presence of 3'-UTR from OXA1 gene on a prokaryotic reporter mRNA and mitochondrial translation in yeast. OXA1 is a nuclear gene that codes for mitochondrial inner membrane insertion protein and its 3'-UTR is shown to direct its mRNA toward mitochondria. It is not clear, however, if this mRNA may also be translated by mitochondria. In the current study, using a β-galactosidase reporter gene, we provide genetic evidence for a correlation between the presence of 3'-UTR of OXA1 on an mRNA and mitochondrial translation in yeast.

Keywords: gene expression; messenger RNA; mitochondria; translation; untranslated regions; yeast

DOI: https://doi.org/10.3390/jof9040445

BMC Biol. 2023 04 24. 21(1): 94

A novel protein encoded by circRsrc1 regulates mitochondrial ribosome assembly and translation during spermatogenesis.

Shu Zhang, Chang Wang, Yue Wang, Hao Zhang, Chen Xu, Yiwei Cheng, Yan Yuan, Jiahao Sha, Xuejiang Guo, Yiqiang Cui.

BACKGROUND: Circular RNAs (circRNAs) are a large class of mammalian RNAs. Several protein products translated by circRNAs have been reported to be involved in the development of various tissues and systems; however, their physiological functions in male reproduction have yet not been explored.
RESULTS: Here, we report an endogenous circRNA (circRsrc1) that encodes a novel 161-amino-acid protein which we named Rsrc1-161aa through circRNA sequencing coupled with mass spectrometry analysis on mouse testicular tissues. Deletion of Rsrc1-161aa in mice impaired male fertility with a significant decrease in sperm count and motility due to dysfunctions of mitochondrial energy metabolism. A series of in vitro rescue experiments revealed that circRsrc1 regulates mitochondrial functions via its encoded protein Rsrc1-161aa. Mechanistically, Rsrc1-161aa directly interacts with mitochondrial protein C1qbp and enhances its binding activity to mitochondrial mRNAs, thereby regulating the assembly of mitochondrial ribosomes and affecting the translation of oxidative phosphorylation (OXPHOS) proteins and mitochondrial energy metabolism.
CONCLUSIONS: Our studies reveal that Rsrc1-161aa protein encoded by circRsrc1 regulates mitochondrial ribosome assembly and translation during spermatogenesis, thereby affecting male fertility.

Keywords: C1qbp; Mitochondrial ribosome; Spermatogenesis; Translation; circRsrc1

DOI: https://doi.org/10.1186/s12915-023-01597-z

Int J Mol Sci. 2023 Apr 17. pii: 7403. [Epub ahead of print]24(8):

Resveratrol Attenuates the Mitochondrial RNA-Mediated Cellular Response to Immunogenic Stress.

Jimin Yoon, Doyeong Ku, Minseok Lee, Namseok Lee, Sung Gap Im, Yoosik Kim.

Human mitochondria contain a circular genome that encodes 13 subunits of the oxidative phosphorylation system. In addition to their role as powerhouses of the cells, mitochondria are also involved in innate immunity as the mitochondrial genome generates long double-stranded RNAs (dsRNAs) that can activate the dsRNA-sensing pattern recognition receptors. Recent evidence shows that these mitochondrial dsRNAs (mt-dsRNAs) are closely associated with the pathogenesis of human diseases that accompany inflammation and aberrant immune activation, such as Huntington's disease, osteoarthritis, and autoimmune Sjögren's syndrome. Yet, small chemicals that can protect cells from a mt-dsRNA-mediated immune response remain largely unexplored. Here, we investigate the potential of resveratrol (RES), a plant-derived polyphenol with antioxidant properties, on suppressing mt-dsRNA-mediated immune activation. We show that RES can revert the downstream response to immunogenic stressors that elevate mitochondrial RNA expressions, such as stimulation by exogenous dsRNAs or inhibition of ATP synthase. Through high-throughput sequencing, we find that RES can regulate mt-dsRNA expression, interferon response, and other cellular responses induced by these stressors. Notably, RES treatment fails to counter the effect of an endoplasmic reticulum stressor that does not affect the expression of mitochondrial RNAs. Overall, our study demonstrates the potential usage of RES to alleviate the mt-dsRNA-mediated immunogenic stress response.

Keywords: Sjögren’s syndrome; dsRNA stress; immunogenic stress; innate immunity; mitochondrial double-stranded RNAs; oligomycin A; resveratrol; tunicamycin

DOI: https://doi.org/10.3390/ijms24087403