A dynamin-like protein in the human malaria parasite plays an essential role in mitochondrial homeostasis and fission during asexual blood stages

Thakur, V.; Singh, S.; Rathore, S.; Muneer, A.; Islam, M.; Datta, G.; Banday, M.; Arora, P.; Hossain, M. E.; Jain, S.; Ali, S.; Mohmmed, A.

doi:10.1101/2024.03.25.586598

bioRxiv · 10.1101/2024.03.25.586598

A dynamin-like protein in the human malaria parasite plays an essential role in mitochondrial homeostasis and fission during asexual blood stages

Thakur, V.·Singh, S.·Rathore, S.·Muneer, A.·Islam, M.·Datta, G.·Banday, M.·Arora, P.·Hossain, M. E.·Jain, S.·Ali, S.·Mohmmed, A.

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Abstract

Malaria parasite harbors a single mitochondrion and its proper segregation during the parasite multiplication is crucial for propagation of the parasite within the host. Mitochondrial fission machinery consists of a number of proteins that associate with mitochondrial membrane during segregation. Here, we have identified a dynamin-like protein in P. falciparum, PfDyn2, and deciphered its role in mitochondrial division, segregation and homeostasis. GFP targeting approach combined with high resolution microscopy studies showed that the PfDyn2 associates with mitochondrial membrane to form a clip/hairpin loop like structure around it at specific sites during mitochondrial division. The C-terminal degradation tag mediated inducible knock-down (iKD) of PfDyn2 resulted in significant inhibition of parasite growth. PfDyn2-iKD hindered mitochondrial development and functioning, decreased mtDNA replication, and induced mitochondrial oxidative-stress, ultimately causing parasite death. Further, treatment of parasites with dynamin specific inhibitors disrupted the recruitment of PfDyn2 on the mitochondria, blocked mitochondrial development, and induced oxidative stress. Regulated overexpression of a phosphorylation mutant of PfDyn2 (Ser-612-Ala) had no effect on the recruitment of PfDyn2 on the mitochondria; normal mitochondrial division and parasite growth showed that phosphorylation/dephosphorylation of this conserved serine residue (Ser612) may not be responsible for regulating recruitment of PfDyn2 to the mitochondrion. Overall, we show essential role of PfDyn2 in mitochondrial dynamics and fission as well as in maintaining its homeostasis during asexual cycle of the parasite.

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Thakur, V., Singh, S., Rathore, S., Muneer, A., Islam, M., Datta, G., Banday, M., Arora, P., Hossain, M. E., Jain, S., Ali, S., Mohmmed, A.. 2024-03-26. A dynamin-like protein in the human malaria parasite plays an essential role in mitochondrial homeostasis and fission during asexual blood stages. https://doi.org/10.1101/2024.03.25.586598

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