A cytosolic IF1 reporter enables real-time visualization of severe mitochondrial membrane damage

作者：Erqing Gao, Liwei Guan, Kehang Zhang, Shuze Qi, Jingxiu Xu, J H Zhang, Tianyi Zhu, Bing Yang, Chonglin Yang, Eric Miska, Mao Zhang, Suhong Xu · 发表于：The Journal of Cell Biology · 年份：2026 · DOI：10.1083/jcb.202511088 · 研究领域：Mitochondrial Function and Pathology、ATP Synthase and ATPases Research、Cell death mechanisms and regulation

Maintenance of mitochondrial integrity is fundamental for cellular survival, yet how cells recognize catastrophic mitochondrial membrane damage remains unknown. Here, we identify MAI-1 as the first genetically encoded reporter of severe mitochondrial membrane damage. MAI-1 is a Caenorhabditis elegans homolog of the ATP synthase inhibitor IF1 that lacks a mitochondrial targeting sequence, resides in the cytosol under basal conditions, but rapidly and irreversibly translocates to severely damaged mitochondria within milliseconds. We validate MAI-1 across diverse injury paradigms and demonstrate that cytosolic IF1 variants from other species exhibit conserved damage-induced recruitment. Mechanistically, MAI-1 recruitment requires the presence of an intact ATP synthase complex. Using MAI-1 as a sensor, we uncover that these severely damaged mitochondria are cleared through the LGG-1-mediated, PINK1/PARKIN-independent lysosomal pathway. Together, our findings establish a powerful tool for visualizing severe mitochondrial membrane damage and reveal a surveillance mechanism dedicated to structural integrity control.