Abstract
Aims/Purpose: The controlled activation of mitophagy has emerged as an exciting therapeutic angle in the treatment of ocular conditions, including diabetic retinopathy and age‐related macular degeneration. Here, we report a novel Muller cell line (MQ‐MG2) for the rapid screening of mitophagy‐activating drugs.Methods: MQ‐MG2 were cloned from spontaneously immortalized primary Muller cells (PMCs) derived from mitophagy reporter (Mito‐QC) mice. Muller glia characteristics were assessed by immunocytochemistry, western blotting, and metabolic flux (Seahorse). The versatility of MQ‐MG2 to detect mitophagy‐activating drugs was tested via pharmacological activation (PINK1‐dependent and PINK1‐independent) and further validated in vivo using Mito‐QC mice.Results: MQ‐MG2 were expanded over 50 passages while retaining expression of Mito‐QC reporter. MQ‐MG2 showed key phenotypic markers of Muller glia, including glutamine synthetase, glial fibrillary acidic protein, Aquaporin 4, and Interleukin‐33. At the bioenergetic level, MQ‐MG2 showed lower basal‐ and ATP‐linked respiration than PMCs, while displaying superior reserve capacity (p < 0.001). Indicative of equivalent glycolytic profiles, extracellular acidification rates (baseline and stressed) remained comparable to PMCs. Importantly, MQ‐MG2 showed excellent sensitivity to screen for mitophagy‐activating drugs, including novel small‐molecules acting through (putative) PINK1‐independent pathways. The versatility of MQ‐MG2 as a drug discovery platform was validated in vivo, where oral administration of PINK1‐independent activator (PIA‐01) amplified mitophagy at the outer retina dose‐dependently.Conclusions: MQ‐MG2 enables rapid and reliable detection of mitophagy‐activating drugs for ocular application. This platform overcomes the limitations of primary cultures, including variability due to cellular senescence and heterogeneity, while minimizing the need for animals in drug discovery.
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