Singh Mithalesh Kumar, Singh Lata, Atilano Shari, Chwa Marilyn, Salimiaghdam Nasim, Kenney M Cristina
Director of Mitochondria Research Laboratory, Gavin Herbert Eye Institute, University of California Irvine, 843 Health Science Rd, Hewitt Hall, Room 2028 , Irvine, CA, 92697, USA.
Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, 75235, USA.
Mol Neurobiol. 2025 Mar 18. doi: 10.1007/s12035-025-04832-6.
Age-related macular degeneration (AMD) is the leading cause of vision impairment among older aged people. Recent studies have indicated that focusing on the underlying mechanism of ferroptosis (a form of iron-dependent cell death) could be crucial in understanding the progression of AMD, as it is strongly linked with inflammation. However, the specific dependence of ferroptosis on the mitochondria in the retinal pigment epithelium (RPE) and its surrounding immune cells remains unclear. In this study, we showed that mitochondria were required for the proliferation and maintenance of the RPE by regulating the expression of genes implicated in both pro- and antiferroptosis activities. Under chemically induced hypoxic conditions, Wt-ARPE-19 cells (basal mitochondrial level) increased the expression of genes linked with antiferroptotic activity. In contrast, rho0-ARPE-19 cells (mitochondria depleted) did not stimulate either pro- or antiferroptosis gene expression. However, diff-ARPE-19 cells (abundant in mitochondria) presented an improved proferroptotic activity. Furthermore, we demonstrated that mitochondria regulated monocyte differentiation into macrophages, resulting in differential expression of pro- and antiferroptotic factors. Through a direct coculture approach, the absence of mitochondria in ARPE-19 cells was shown to influences monocyte differentiation toward an inflammatory phenotype. This differentiation might increase ferroptosis activity. Transmitochondrial cybrids derived from patients with dry AMD and age-matched controls without dry AMD presented elevated mtDNA copy numbers, leading to increased ferritinophagy and increased levels of polyunsaturated fatty acids. These data highlighted that ferroptosis was partly regulated by mitochondria and that understanding the mechanisms governing the relationship between mitochondria and ferroptosis may open new potential avenues for managing dry AMD.
年龄相关性黄斑变性（AMD）是老年人视力损害的主要原因。最近的研究表明，关注铁死亡（一种铁依赖性细胞死亡形式）的潜在机制对于理解AMD的进展可能至关重要，因为它与炎症密切相关。然而，视网膜色素上皮（RPE）及其周围免疫细胞中铁死亡对线粒体的具体依赖性仍不清楚。在本研究中，我们表明线粒体通过调节与促铁死亡和抗铁死亡活性相关的基因表达，对RPE的增殖和维持是必需的。在化学诱导的缺氧条件下，Wt-ARPE-19细胞（基础线粒体水平）增加了与抗铁死亡活性相关的基因表达。相比之下，rho0-ARPE-19细胞（线粒体耗尽）既不刺激促铁死亡基因表达也不刺激抗铁死亡基因表达。然而，diff-ARPE-19细胞（线粒体丰富）表现出增强的促铁死亡活性。此外，我们证明线粒体调节单核细胞分化为巨噬细胞，导致促铁死亡和抗铁死亡因子的差异表达。通过直接共培养方法，ARPE-19细胞中线粒体的缺失被证明会影响单核细胞向炎症表型的分化。这种分化可能会增加铁死亡活性。来自干性AMD患者和年龄匹配的无干性AMD对照的线粒体杂交细胞呈现出线粒体DNA拷贝数升高，导致铁蛋白自噬增加和多不饱和脂肪酸水平升高。这些数据强调铁死亡部分受线粒体调节，并且了解线粒体与铁死亡之间关系的调控机制可能为干性AMD的治疗开辟新的潜在途径。
