Single-cell transcriptome reveals diversity of Müller cells with different metabolic-mitochondrial signatures in normal and degenerated macula

Müller cell is the most abundant glial cell in mammalian retina, supporting the functions of photoreceptors and other retinal neurons via maintaining environmental homeostasis. In response to injury and/or neuronal degeneration, Müller cells undergo morphological and functional alternations, known as reactive gliosis documented in multiple retinal diseases, including age-related macular degeneration (AMD), retinitis pigmentosa, diabetic retinopathy, and traumatic retinal detachment. But the functional consequences of Müller glia cell reactivation or even the regulatory networks of the retinal gliosis are still controversial. In this study, we reveal different subpopulations of Müller cells with distinct metabolic-mitochondrial signatures by integrating single cell transcriptomic data from Early AMD patients and healthy donors. Our results show that a portion of Müller cells exhibits low mitochondrial DNA (mtDNA) expressions, reduced protein synthesis, impaired homeostatic regulation, decreased proliferative ability but enhanced proangiogenic function. Interestingly, the major alternation of Müller cells in Early AMD retina is the change of subpopulation abundance, rather than generation of new subcluster. Transcription factor enrichment analysis further highlights the key regulators of metabolic-mitochondrial states of Müller glias in Early AMD patients especially. Our study demonstrates new characteristics of retinal gliosis associated with Early AMD and suggests the possibility to prevent degeneration by intervening mitochondrial functions of Müller cells.