bims-micpro 2025-07-27 papers

Pathol Res Pract. 2025 Jul 17. pii: S0344-0338(25)00329-2. [Epub ahead of print]273 156136

The unexplored Nexus: Mitochondria derived microproteins and Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder and mainly occurs in people above the age of 60 years. It is defined by the progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, which results in the classic motor symptoms. Though aggregation of alpha-synuclein and Lewy body formation are still the core of the disease pathogenesis, PD pathogenesis is complex with mitochondrial dysfunction, oxidative stress, neuroinflammation, impaired autophagy, and endoplasmic reticulum (ER)-Golgi stress. Of these, mitochondrial dysfunction has been the focus of special interest because of its key function in energy metabolism and generation of reactive oxygen species (ROS), which can hasten the neuronal damage. Over the past few years, mitochondrial-derived peptides (MDPs), also k/a mitochondrial microproteins such as Humanin, Small Humanin-Like Peptides (SHLPs), and Mitochondrial Open Reading Frame of the 12S rRNA type-c (MOTS-c) have been identified as new hope for modulating cellular stress responses. Their therapeutic opportunities to impact major pathogenic processes in PD, including inflammation, oxidative stress, and metabolic dysfunction, make them new targets for disease-modifying therapies. With the escalating load of PD and the limitation of existing symptomatic therapies, novel molecular targets need to be explored urgently. Research into the mechanisms involving MDPs in PD not only enhances the insight into disease mechanisms but could potentially lead the way toward next-generation therapies. This article is intended to thoroughly review the role of MDPs in PD pathogenesis and highlight their importance as novel therapeutic agents. With the growing burden of PD and the absence of disease-modifying therapies, exploring novel mitochondrial signaling pathways offers an urgently needed therapeutic direction.

Keywords: Humanin; MOTS-c; Mitochondrial peptides; Parkinson’s disease; SHLP

DOI: https://doi.org/10.1016/j.prp.2025.156136

J Biol Chem. 2025 Jul 21. pii: S0021-9258(25)02358-0. [Epub ahead of print] 110507

A novel protein encoded by circTUBGCP3 blocks ferroptosis and promotes gastric cancer progression.

Shanshan Chang, Xianli Fu, Longquan Xiang, Yuqian Yuan, Siyu Xiao, Lehua Peng, Xiaoya Xie, Xinyi Kang, Xianling Feng, Hassan Ashktorab, Yin Peng, Zhe Jin, Xiaojing Zhang.

Circular RNAs play significant roles in the development and progression of various cancers through diverse mechanisms, including the translation of novel proteins. Ferroptosis, a recently identified form of cell death, is associated with tumorigenesis in several cancers; however, its pathological mechanisms in gastric cancer (GC) remain unclear. Here, we found that circTUBGCP3 expression was elevated in GC tissues compared with normal gastric tissues. Moreover, circTUBGCP3 can be translated into a previously undescribed protein, TUBGCP3-230aa. In vitro and in vivo functional analyses demonstrated that both circTUBGCP3 and TUBGCP3-230aa promote rapid GC cell proliferation, with TUBGCP3-230aa exerting independent biological effects. Enolase 1 (ENO1), a glycolytic enzyme, was identified as an interacting partner of TUBGCP3-230aa, leading to activation of the glycolytic pathway and inhibition of ferroptosis in GC cells in vitro and in vivo. Mechanistically, TUBGCP3-230aa stabilizes ENO1 through posttranslational regulation, thereby repressing ferroptosis. Together, our results identify circTUBGCP3 and TUBGCP3-230aa as potential biomarkers for GC and uncover a novel mechanism of ferroptosis regulation, which may represent a promising therapeutic target. Furthermore, our findings highlight a critical moonlighting function of ENO1 in GC and underscore its potential as a novel target for cancer therapy.

Keywords: TUBGCP3-230aa; circTUBGCP3; ferroptosis; gastric cancer; novel protein

DOI: https://doi.org/10.1016/j.jbc.2025.110507

Biochemistry. 2025 Jul 23.

The ERVK3-1 Microprotein Interacts with the HUSH Complex.

Ayodya Jayatissa, Nadiya Jaunbocus, Betel Erkalo, Kevin Jiang, Shu-Jian Zheng, Haomiao Su, Lichong Yan, Jin-Young Choi, Joan Vaughan, Antonella Bacchiocchi, Zhenkun Na, Xiongwen Cao, Ruth Halaban, Alan Saghatelian, Joseph Craft, Y Grace Chen, Sarah A Slavoff.

Human endogenous retroviruses (hERVs) are noninfectious molecular remnants of ancient exogenous retroviruses that now make up 8% of the human genome. The ubiquitously expressed human ERVK3-1 locus was recently annotated as encoding a 109-amino acid endogenous retroviral Rec microprotein. However, because this locus was thought to be noncoding until recently, it is currently unknown whether the ERVK3-1 microprotein has a function in human cells. We demonstrate that the ERVK3-1 microprotein interacts with PPHLN1, a component of the HUSH complex. The HUSH complex promotes transcriptional repression of intron-less genes, which include parasitic genomic elements such as retrotransposons and endogenous retroviruses. We show that the ERVK3-1 microprotein is essential for transcriptional repression of previously identified HUSH target genes. We thus suggest that the ERVK3-1 Rec microprotein contributes to sensing or regulation of target gene expression by the HUSH complex.

DOI: https://doi.org/10.1021/acs.biochem.5c00023