Djalalvandi Andre, Takeda Keisuke, Grespi Francesca, Fan Hualin, Fonseca Tiago Branco, Nogara Leonardo, Sharifi Saman, Barison Carlotta, Semenzato Martina, Omori Akiko, Cerutti Raffaele, Steffan Davide, Tsansizi Lorenza, Balmaceda Valeria, Alan Lukas, Bean Camilla, Blaauw Bert, Viscomi Carlo, Scorrano Luca
Department of Biology, University of Padova, Via U. Bassi 58B, 35121 Padova, Italy; Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.
Veneto Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy; Department of Biomedical Sciences University of Padova, Via U. Bassi 58B, 35121 Padova, Italy; Department of Pharmaceutical Sciences, University of Padova, Via Marzolo, 5 35131 Padova, Italy.
Cell Rep Med. 2025 Aug 19;6(8):102248. doi: 10.1016/j.xcrm.2025.102248. Epub 2025 Jul 24.
Alterations in mitochondrial ultrastructure and reduced levels of the crista-shaping protein Opa1 are key features of mitochondrial myopathies and aging. We identify and characterize a biological therapy that improves mitochondrial and disuse myopathy models by boosting Opa1 levels. In silico analysis identifies microRNAs (miRNAs) 128-3p and 148/152-3p family as conserved modulators of OPA1 transcription and elevated in various muscle disorders. These miRNAs target the 3' UTR of murine and human OPA1, reducing its mRNA and protein levels, causing mitochondrial fragmentation and crista disorganization. Genetic experiments confirm that their mitochondrial effects rely on 3' UTR binding. In mitochondrial disease patient cells and murine models, elevated OPA1-specific miRNA levels are reduced by antagonistic miRNAs (Opantimirs), which restore mitochondrial ultrastructure, morphology, and function. In vivo, Opantimirs correct mitochondrial ultrastructure and fiber size in muscles of denervated and Cox15-ablated mice, improving strength in the latter. Thus, biopharmacological correction of the mitochondrial ultrastructure can ameliorate mitochondrial myopathies.
线粒体超微结构的改变以及嵴形成蛋白Opa1水平的降低是线粒体肌病和衰老的关键特征。我们鉴定并表征了一种通过提高Opa1水平来改善线粒体和废用性肌病模型的生物疗法。计算机分析确定了微小RNA（miRNA）128 - 3p和148/152 - 3p家族是OPA1转录的保守调节因子，且在各种肌肉疾病中升高。这些miRNA靶向小鼠和人类OPA1的3'非翻译区（UTR），降低其mRNA和蛋白质水平，导致线粒体碎片化和嵴紊乱。遗传学实验证实它们的线粒体效应依赖于3'UTR结合。在线粒体疾病患者细胞和小鼠模型中，拮抗miRNA（Opantimirs）可降低升高的OPA1特异性miRNA水平，恢复线粒体超微结构、形态和功能。在体内，Opantimirs可纠正去神经支配和Cox15基因敲除小鼠肌肉中的线粒体超微结构和纤维大小，改善后者的力量。因此，线粒体超微结构的生物药理学纠正可改善线粒体肌病。
