In vivo imaging of mitochondrial DNA mutations using an integrated nano Cas12a sensor

Yanan Li, Yonghua Wu, Ru Xu, Jialing Guo, Fenglei Quan, Yongyuan Zhang, Di Huang, Yiran Pei, Hua Gao, Wei Liu, Junjie Liu, Zhenzhong Zhang (), Ruijie Deng (), Jinjin Shi () and Kaixiang Zhang ()
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Yanan Li: Zhengzhou University
Yonghua Wu: Zhengzhou University
Ru Xu: Zhengzhou University
Jialing Guo: Zhengzhou University
Fenglei Quan: Zhengzhou University
Yongyuan Zhang: Zhengzhou University
Di Huang: Zhengzhou University
Yiran Pei: Zhengzhou University
Hua Gao: Zhengzhou University
Wei Liu: Zhengzhou University
Junjie Liu: Zhengzhou University
Zhenzhong Zhang: Zhengzhou University
Ruijie Deng: Sichuan University
Jinjin Shi: Zhengzhou University
Kaixiang Zhang: Zhengzhou University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Mutations in mitochondrial DNA (mtDNA) play critical roles in many human diseases. In vivo visualization of cells bearing mtDNA mutations is important for resolving the complexity of these diseases, which remains challenging. Here we develop an integrated nano Cas12a sensor (InCasor) and show its utility for efficient imaging of mtDNA mutations in live cells and tumor-bearing mouse models. We co-deliver Cas12a/crRNA, fluorophore-quencher reporters and Mg2+ into mitochondria. This process enables the activation of Cas12a’s trans-cleavage by targeting mtDNA, which efficiently cleave reporters to generate fluorescent signals for robustly sensing and reporting single-nucleotide variations (SNVs) in cells. Since engineered crRNA significantly increase Cas12a’s sensitivity to mismatches in mtDNA, we can identify tumor tissue and metastases by visualizing cells with mutant mtDNAs in vivo using InCasor. This CRISPR imaging nanoprobe holds potential for applications in mtDNA mutation-related basic research, diagnostics and gene therapies.

Date: 2023
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DOI: 10.1038/s41467-023-43552-0

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