Gaertner Kateryna, Terzioglu Mügen, Michell Craig, Tapanainen Riikka, Pohjoismäki Jaakko, Dufour Eric, Saari Sina
Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
Department of Environmental and Biological Sciences, University of Eastern Finland, Joensuu, Finland; King Abdullah University of Science and Technology, Makkah, Saudi Arabia.
Biochim Biophys Acta Bioenerg. 2025 Apr 1;1866(2):149530. doi: 10.1016/j.bbabio.2024.149530. Epub 2024 Dec 2.
The temperate climate-adapted brown hare (Lepus europaeus) and the cold-adapted mountain hare (Lepus timidus) are closely related and interfertile species. However, their skin fibroblasts display distinct gene expression profiles related to fundamental cellular processes. This indicates important metabolic divergence between the two species. Through targeted metabolomics and metabolite tracing, we identified species-specific variations in glycerol 3-phosphate (G3P) metabolism. G3P is a key metabolite of the G3P shuttle, which transfers reducing equivalents from cytosolic NADH to the mitochondrial electron transport chain (ETC), consequently regulating glycolysis, lipid metabolism, and mitochondrial bioenergetics. Alterations in G3P metabolism have been implicated in multiple human pathologies including cancer and diabetes. We observed that mountain hare mitochondria exhibit elevated G3P shuttle activity, alongside increased membrane potential and decreased mitochondrial temperature. Silencing mitochondrial G3P dehydrogenase (GPD2), which couples the conversion of G3P to the ETC, uncovered its species-specific role in controlling mitochondrial membrane potential and highlighted its involvement in skin fibroblast thermogenesis. Unexpectedly, GPD2 silencing enhanced wound healing and cell proliferation rates in a species-specific manner. Our study underscores the pivotal role of the G3P shuttle in mediating physiological, bioenergetic, and metabolic divergence between these hare species.
适应温带气候的棕兔（欧洲野兔）和适应寒冷气候的山兔（林兔）是亲缘关系密切且可杂交繁殖的物种。然而，它们的皮肤成纤维细胞显示出与基本细胞过程相关的独特基因表达谱。这表明这两个物种之间存在重要的代谢差异。通过靶向代谢组学和代谢物追踪，我们确定了甘油 3-磷酸（G3P）代谢中的物种特异性差异。G3P 是 G3P 穿梭系统的关键代谢物，该系统将还原当量从胞质 NADH 转移到线粒体电子传递链（ETC），从而调节糖酵解、脂质代谢和线粒体生物能量学。G3P 代谢的改变与包括癌症和糖尿病在内的多种人类疾病有关。我们观察到山兔线粒体表现出升高的 G3P 穿梭活性，同时膜电位增加，线粒体温度降低。沉默将 G3P 转化与 ETC 偶联的线粒体甘油 3-磷酸脱氢酶（GPD2），揭示了其在控制线粒体膜电位中的物种特异性作用，并突出了其在皮肤成纤维细胞产热中的作用。出乎意料的是，GPD2 沉默以物种特异性方式提高了伤口愈合和细胞增殖率。我们的研究强调了 G3P 穿梭系统在介导这些兔类物种之间的生理、生物能量和代谢差异方面的关键作用。
