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bioRxiv · 10.1101/2025.08.01.667885

Mammalian cells evacuate and shelter mitochondrial DNA from destruction following hypoxia response-induced mitophagy

Kamegai, R.·Uenosono, A.·Ikeda, F.·Ohta, K.·Yanagitani, K.
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Abstract

Cells use a specialized process called mitophagy to degrade mitochondria, and the conditions that induce mitophagy can endanger mitochondrial DNA (mtDNA). Here, we report a novel mechanism by which cells undergoing hypoxia response (HR)-induced mitophagy protect their mtDNA from destruction by segregating it into large mitochondria (Mito-L). Using time-lapse imaging, we found that Mito-L are formed when mitochondria undergo tubular-to-spherical transitions and then fuse together. Under HR-activating conditions, we found the mitophagy process itself is essential for Mito-L formation. When we fragmented mitochondria prior to inducing the HR, we observed fewer Mito-L and more mtDNA degradation. Thus, mammalian cells protect mtDNA against excessive mitophagy induced by HR, thereby preventing the loss of the genetic information. Hypoxia response-induced mitophagy triggers cells to shelter mitochondrial DNA (70 characters)

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Kamegai, R., Uenosono, A., Ikeda, F., Ohta, K., Yanagitani, K.. 2025-08-02. Mammalian cells evacuate and shelter mitochondrial DNA from destruction following hypoxia response-induced mitophagy. https://doi.org/10.1101/2025.08.01.667885

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