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Despite notable progress in reducing malaria-related morbidity and mortality, the rise of drug-resistant Plasmodium falciparum strains continues to undermine eradication efforts. In this context, the parasite\u2019s mitochondrion has emerged as a promising target for novel antimalarial therapies due to its essential role in parasite viability throughout all life cycle stages and its marked structural and biochemical differences from the human counterpart. This review highlights recent advances in the development of compounds targeting mitochondrial function in P. falciparum and discusses the utility of Saccharomyces cerevisiae as a powerful model organism for antimalarial drug discovery. Owing to its shared eukaryotic features, genetic tractability, and capacity for heterologous expression of parasite mitochondrial proteins, S. cerevisiae offers a cost-effective and experimentally accessible platform for elucidating drug mechanisms and accelerating therapeutic development.<\/jats:p>","DOI":"10.3390\/ijms26189150","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T12:33:32Z","timestamp":1758285212000},"page":"9150","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting Mitochondrial Function in Plasmodium falciparum: Insight into Antimalarial Drugs and the Emerging Role of Saccharomyces cerevisiae as a Model System"],"prefix":"10.3390","volume":"26","author":[{"given":"Sara","family":"Greco","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, I-73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0165-7920","authenticated-orcid":false,"given":"Graziana","family":"Assalve","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, I-73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7118-1994","authenticated-orcid":false,"given":"Paola","family":"Lunetti","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Salento, I-73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kassoum","family":"Kayentao","sequence":"additional","affiliation":[{"name":"Parasites and Microbes Research and Training Center, University of Science, Techniques and Technologies, Point G, Bamako P.O. 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