A neuron‐specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

Author:

Sheng Hanxuan1ORCID,Lu Dan2,Qi Xiaolong2,Ling Yahao1,Li Jing2,Zhang Xu2,Dong Wei1,Chen Wei1,Gao Shan2,Gao Xiang2,Zhang Li2,Zhang Lianfeng1ORCID

Affiliation:

1. Key Laboratory of Human Disease Comparative Medicine, National Health Commission of China (NHC) Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China

2. Beijing Engineering Research Center for Experimental Animal Models of Human Diseases Institute of Laboratory Animal Science, Peking Union Medical College, Chinese Academy of Medical Sciences Beijing China

Abstract

AbstractBackgroundMultiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death.MethodsWe generated neuron‐specific Isca1 knockout rat (Isca1flox/flox ‐NeuN‐Cre) using CRISPR‐Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons.ResultsThis study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis.ConclusionsThis rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.

Funder

National Basic Research Program of China

National Natural Science Foundation of China

Publisher

Wiley

Subject

Medical Laboratory Technology,Veterinary (miscellaneous),Molecular Biology,Biochemistry,Medicine (miscellaneous)

Reference39 articles.

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2. A review of multiple mitochondrial dysfunction syndromes, syndromes associated with defective Fe‐S protein maturation;Lebigot E;Biomedicine,2021

3. Mechanistic concepts of iron-sulfur protein biogenesis in Biology

4. Protein networks in the maturation of human iron–sulfur proteins

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