A novel chimeric molecule, namely autophagy-targeting chimera (AUTAC), is the first degrader using the autophagy mechanism. AUTAC consists of a guanine tag and a specific binder of an intracellular target of interest. In addition, AUTAC can penetrate cell membranes, and degrade fragmented mitochondria as well as proteins. Mitochondria not only produce the majority of cellular energy, but also play an important role in cellular physiology, including apoptosis. Therefore, mitochondrial dysfunction is related to a series of age-related diseases, such as neurodegenerative diseases, cancer and diabetes. More importantly, Mitochondrial-targeted AUTAC (mito-AUTAC) accelerates the removal of dysfunctional mitochondria and the biogenesis of functionally normal mitochondria in fibroblasts.

Hirokazu Arimoto et al. prepares the chimeric molecule AUTAC4 to deliver a guanine tag to the mitochondrial membrane. AUTAC4 is a mitochondria-targeting AUTAC that promotes mitophagy of small, fragmented mitochondria. Moreover, AUTAC4 can induce K63-linked polyubiquitination. At a concentration of 10 μM, it reduces the loss of mitochondrial membrane potential and apoptosis induced by CCCP treatment. Except for, the intracellular ATP level after CCCP treatment is also maintained by AUTAC4. AUTAC4 not only inhibits the release of cytochrome c into the cytoplasm, but also inhibits the cleavage of pro-caspase 3. In addition, it can also rescue cells with acute mitochondrial damage by promoting mitochondrial autophagy.

In Down syndrome (DS) cells, AUTAC4 treatment can restore themitochondrial membrane potential and ATP production. And it induces mitophagy in Detroit 532 cells ~24-72 h after treatment. Notably, the mitophagy induced by AUTAC4 treatment also increased the level of PPARGC1A/PGC-1α, which is the main regulator of mitochondrial biogenesis.

To sum up, AUTAC4 is a mitochondria-targeting autophagy-targeting chimera, which can be used for the study of mitochondrial dysfunction.

[1] Daiki Takahashi, et al. Mol Cell. 2019 Dec 5;76(5):797-810.e10.

[2] Daiki Takahashi, et al. Autophagy. 2020 Apr;16(4):765-766.