Isca1, or Iron-sulfur cluster assembly 1, is an iron-sulfur (Fe/S) carrier protein crucial for mitochondrial iron-sulfur cluster (Fe-S) biogenesis [4]. It plays a key role in the maturation of mitochondrial [4Fe-4S] proteins, a process that is integral to the function of many metabolic and respiratory enzymes [2,3,6].

Gene knockout models have provided valuable insights into Isca1 function. In rats, global Isca1 knockout causes early embryonic death at 8.5 days, with abnormal development and changes in mitochondrial respiratory chain complex proteins [4]. Neuron-specific Isca1 knockout in rats leads to multiple mitochondrial dysfunction syndromes (MMDS5), including developmental retardation, epilepsy, memory impairment, neuronal death, mitochondrial damage, and reduced ATP production [1]. Myocardium-specific Isca1 knockout in rats results in iron metabolism disorder, myocardial oncosis, and eventually heart failure and death [5]. In a patient with infantile-onset leukodystrophy, an ISCA1 mutation led to defects in mitochondrial [4Fe-4S] proteins [6].

In conclusion, Isca1 is essential for mitochondrial Fe-S biogenesis and the proper function of mitochondria. Gene knockout models in rats have revealed its significance in the nervous system, heart development, and overall embryonic development, and have provided valuable research models for understanding MMDS and related mitochondrial diseases [1,4,5,6].

References:

1. Sheng, Hanxuan, Lu, Dan, Qi, Xiaolong, Zhang, Li, Zhang, Lianfeng. . A neuron-specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes. In Animal models and experimental medicine, 6, 155-167. doi:10.1002/ame2.12318. https://pubmed.ncbi.nlm.nih.gov/37140997/

2. Suraci, Dafne, Saudino, Giovanni, Nasta, Veronica, Ciofi-Baffoni, Simone, Banci, Lucia. 2021. ISCA1 Orchestrates ISCA2 and NFU1 in the Maturation of Human Mitochondrial [4Fe-4S] Proteins. In Journal of molecular biology, 433, 166924. doi:10.1016/j.jmb.2021.166924. https://pubmed.ncbi.nlm.nih.gov/33711344/

3. Beilschmidt, Lena Kristina, Ollagnier de Choudens, Sandrine, Fournier, Marjorie, Puccio, Hélène, Martelli, Alain. 2017. ISCA1 is essential for mitochondrial Fe4S4 biogenesis in vivo. In Nature communications, 8, 15124. doi:10.1038/ncomms15124. https://pubmed.ncbi.nlm.nih.gov/28492233/

4. Yang, Xinlan, Lu, Dan, Zhang, Xu, Ma, Yuanwu, Zhang, Lianfeng. 2019. Knockout of ISCA1 causes early embryonic death in rats. In Animal models and experimental medicine, 2, 18-24. doi:10.1002/ame2.12059. https://pubmed.ncbi.nlm.nih.gov/31016283/

5. Ling, Yahao, Yang, Xinlan, Zhang, Xu, Lu, Dan, Zhang, Lianfeng. 2022. Myocardium-specific Isca1 knockout causes iron metabolism disorder and myocardial oncosis in rat. In Life sciences, 297, 120485. doi:10.1016/j.lfs.2022.120485. https://pubmed.ncbi.nlm.nih.gov/35304126/

6. Torraco, Alessandra, Stehling, Oliver, Stümpfig, Claudia, Lill, Roland, Carrozzo, Rosalba. . ISCA1 mutation in a patient with infantile-onset leukodystrophy causes defects in mitochondrial [4Fe-4S] proteins. In Human molecular genetics, 27, 2739-2754. doi:10.1093/hmg/ddy183. https://pubmed.ncbi.nlm.nih.gov/29767723/