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IPD3377 |
Dynamic metabolic remodelling and mitochondrial import machinery facilitate cellular stress survival and artemisinin resistance/tolerance in human malaria parasite Plasmodium falciparum. |
Dr. Asif Mohmmed |
The organellar stress response has emerged as an important factor influencing the survival of Plasmodium falciparum under cellular stress and artemisinin exposure, thus playing critical role in drug resistance/tolerance. However, the mechanisms by which mitochondria respond to cellular stress and their intersection with artemisinin resistance remain to be understood. Here,...
The organellar stress response has emerged as an important factor influencing the survival of Plasmodium falciparum under cellular stress and artemisinin exposure, thus playing critical role in drug resistance/tolerance. However, the mechanisms by which mitochondria respond to cellular stress and their intersection with artemisinin resistance remain to be understood. Here, we analysed mitochondrial stress-induced organelle dynamics and quantitative proteomic changes in the parasite, revealing a dynamic stress response. In the initial phase, parasites activate a reversible, pro-survival response characterised by glycolytic compensation, suppressed TCA cycle activity, and proteostasis remodelling. A subsequent ‘critical survival phase’ activates organelle repair pathways, marked by selective upregulation of the mitochondrial protein import machinery, including PfMPPβ, a key regulator of mitochondrial protein maturation. Ablation of PfMPPβ causes severe growth inhibition, disrupts mitochondrial development and function, and alters metabolic flux. Ultra-Expansion Microscopy (UExM) revealed a loss of coordinated alignment among mitochondria, tubulin, and daughter nuclear segregation, which results in defective merozoite segregation. Substratetrap proteomics showed that PfMPPβ processes important mitochondrial proteins, including the ATPsynthase complex, TCAmetabolite transporters, and the BCKDH complex, thereby suggesting a functional link to pro-survival responses. Importantly, loss of PfMPPβ function rendered both wild-type and artemisinin-resistant parasites hypersensitive to organellar stress and to dihydroartemisinin, suggesting that PfMPPβ-mediated organelle homeostasis is critical for the organelle stress response that underlies artemisinin resistance. Overall, our findings elucidate the association between mitochondrial stress response and drug tolerance, thus identifying PfMPPβ as a potential target for combating artemisinin resistance/tolerance in malaria.
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International Centre for Genetic Engineering and Biotechnology, New Delhi, Delhi, India |
Bottom-up |
2030-09-30 |
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