MITF promotes MFN2-dependent mitochondrial fusion to protect retinal pigment epithelial cells from mitochondrial damage.

There is growing indication that protecting the retinal pigment epithelium (RPE) against mitochondrial damage is crucial for preventing RPE cell dysfunction and retinal degeneration. However, the molecular mechanisms remain largely unknown. Here, we show that microphthalmia-associated transcription factor (MITF), a potent antioxidant inducer in RPE, promotes mitochondrial fusion in RPE cells and protects them from mitochondrial uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced mitochondrial damage in ARPE-19 or mouse primary RPE cells ex vivo and Mitf heterozygous mice (Mitf-/+), Mitf-overexpressing transgenic mice (Dct-Mitf) or AAV mediated MITF overexpression mice in vivo. Mechanistically, MITF directly binds to the promoter of Mitofusin 2 (MFN2), a mitochondrial membrane protein that participates in mitochondrial fusion, and activates its transcription. Conversely, the knockdown of MFN2 neutralized the effects of MITF on mitochondrial fusion and mitochondrial damage protection. Intravitreal injection of mitochondria-targeted SkQ-1 nanoparticles effectively protects RPE cells from CCCP-induced damage in the Mitf-/+ mice in vivo. These findings suggest that MITF has an important role in regulating mitochondrial fusion in RPE cells and provides new insights into understanding the mechanisms of MITF deficiency induced RPE abnormalities and retinal degeneration.