Zhao Xue, Makia Mustafa S, Naash Muna I, Al-Ubaidi Muayyad R
Department of Biomedical Engineering, University of Houston, 3517 Cullen Blvd., Houston, TX, 77204, USA.
Redox Biol. 2025 Jul 16;85:103772. doi: 10.1016/j.redox.2025.103772.
The retina, a metabolically active tissue, relies on adequate flavin levels for optimal function. Our previous research demonstrated that ablation of RTBDN, a retina-specific riboflavin binding protein, plays a pivotal role in maintaining flavin levels, leading to progressive retinal degeneration. This raises the fundamental question of how riboflavin deficiency impacts retinal structure and function. We have previously evaluated an adult diet-induced model of riboflavin deficiency and showed that lack of flavins resulted in severe functional and structural deficits in the neural retina and retinal pigment epithelium with increased oxidative stress and metabolic dysregulation. Ariboflavinosis resulting from mutations in riboflavin transporters manifests early in life and is treatable with riboflavin supplementation. To mimic ariboflavinosis, we established an early-onset dietary model. At postnatal day 30, we observed a pronounced retinal phenotype characterized by early decline in cone function and subsequent loss of cone photoreceptors, while rods remained unaffected. Notably, RTBDN exhibited a biphasic response to early ariboflavinosis: initially upregulated, suggesting a protective role in maintaining retinal flavin levels, but decreased as deficiency persisted with subsequent photoreceptor functional decline. Riboflavin supplementation partially ameliorated these phenotypes by restoring retinal flavin and RTBDN levels, resulting in improvements in retinal structure and function. However, some cellular changes in the RPE remained irreversible and cone count was not restored. These findings underscore the critical roles of riboflavin and RTBDN in maintaining retinal and RPE health and highlight the importance of early detection and intervention for optimal therapeutic outcomes.
视网膜是一种代谢活跃的组织，其最佳功能依赖于充足的黄素水平。我们之前的研究表明，视网膜特异性核黄素结合蛋白RTBDN的缺失在维持黄素水平方面起着关键作用，导致进行性视网膜变性。这就提出了一个基本问题，即核黄素缺乏如何影响视网膜的结构和功能。我们之前评估了一种成年期饮食诱导的核黄素缺乏模型，结果表明，黄素缺乏导致神经视网膜和视网膜色素上皮出现严重的功能和结构缺陷，同时氧化应激增加和代谢失调。由核黄素转运蛋白突变引起的核黄素缺乏症在生命早期就会出现，补充核黄素可对其进行治疗。为了模拟核黄素缺乏症，我们建立了一种早发性饮食模型。在出生后第30天，我们观察到一种明显的视网膜表型，其特征是视锥细胞功能早期下降，随后视锥光感受器丧失，而视杆细胞未受影响。值得注意的是，RTBDN对早期核黄素缺乏症表现出双相反应：最初上调，表明在维持视网膜黄素水平方面具有保护作用，但随着缺乏持续以及随后光感受器功能下降而降低。补充核黄素通过恢复视网膜黄素和RTBDN水平部分改善了这些表型，从而使视网膜结构和功能得到改善。然而，视网膜色素上皮的一些细胞变化仍然是不可逆的，视锥细胞数量也没有恢复。这些发现强调了核黄素和RTBDN在维持视网膜和视网膜色素上皮健康方面的关键作用，并突出了早期检测和干预对于实现最佳治疗效果的重要性。
