Garcia-Llorca, A. | Search bioRxiv

bioRxiv2026

MITF is essential for autophagy in the retinal pigment epithelium

The Microphthalmia-associated transcription factor (MITF) plays a critical role in retinal pigment epithelium (RPE) development and function. Dysfunctional autophagy and lysosomal degradation in the RPE have been implicated in age-related retinal degeneration, yet the contribution of MITF to these pathways remains incompletely understood. Here, we show that reduced Mitf expression impairs autophagy in mouse and human RPE cells. Primary RPE cells from Mitfmi-vga9/+ heterozygotes mice displayed altered autophagic flux characterized by accumulation of LC3B-II and p62, while MITF knockdown in human ARPE-19 cells promoted autophagosome accumulation. Ultrastructural analysis further revealed age-dependent accumulation of autolysosomes and lipofuscin-like granules in mutant RPE cells. In addition, expression of autophagy-related genes was altered in mutant RPE tissue, supporting disrupted lysosomal-autophagic homeostasis. Together, our findings identify MITF as an important regulator of autophagy in the RPE and suggest that impaired MITF-dependent homeostasis may contribute to retinal degeneration.

cell biology↗

bioRxiv2025

Cell-Intrinsic Vulnerability and Immune Activation Cooperate to Drive Degeneration in a Mitochondrial Complex I Deficiency Model of Optic Neuropathy

Mitochondrial dysfunction is a central hallmark of many optic neuropathies, yet the mechanisms linking intrinsic metabolic stress to retinal ganglion cell (RGC) degeneration remain unclear. To bridge this gap, we developed conditional transgenic models targeting the mitochondrial complex I subunit Ndufs4 in the retina. Broad deletion of Ndufs4 in the retina resulted in vision loss, progressive RGC degeneration, and pronounced immune activation before overt RGC death. Strikingly, depletion of myeloid cells significantly preserved RGCs, demonstrating that inflammation is not simply a downstream consequence but a participant in the degeneration process. To further distinguish between intrinsic and extrinsic mechanisms, we generated a mosaic model in which only subsets of retinal cells lacked Ndufs4. In this paradigm, the degeneration first appeared selectively in mutant regions, suggesting that mitochondrial impairment within RGCs is necessary to initiate vulnerability. At later stages, however, the degeneration extended beyond mutant territories, highly suggestive of a propagation through non-cell autonomous processes. Together, these findings support a model in which mitochondrial dysfunction creates the conditions for neuronal vulnerability, while immune responses govern the timing and extent of cell loss. This framework explains the consistent co-occurrence of metabolic deficits and neuroinflammation in optic neuropathies and highlights the importance of their interactions in disease progression. By clarifying the intersection of intrinsic and extrinsic mechanisms, this work advances our understanding of RGC degeneration and provides a conceptual basis for deciphering pathogenic processes across diverse optic neuropathies.

neuroscience↗