{
  "abstract": "Introduction: Protozoan parasites continue to impose a major burden on human and veterinary health, while emerging drug resistance increasingly limits treatment options. Identifying conserved biological vulnerabilities shared across diverse parasites may facilitate the development of new therapeutic strategies. Here, we investigated whether mitochondrial electron transport represents a common metabolic vulnerability in drug-resistant protozoan pathogens.\n\nMethods: The Medicines for Malaria Venture Global Health Priority Box (GHPB) was screened against Theileria annulata-infected cells to identify compounds affecting parasite survival. Rotenone was evaluated using cell viability assays, flow cytometry, mitochondrial membrane potential, reactive oxygen species (ROS) detection, apoptosis assays, transcriptomic profiling, drug combination studies, and comparative bioinformatic analyses.\n\nResults: Rotenone selectively inhibited T. annulata-infected cells (IC50 = 1.30 ± 0.27 μM) while sparing uninfected cells, retained efficacy against buparvaquone-resistant cells, and showed activity against Leishmania donovani (IC50 = 10.12 ± 0.98 μM), Entamoeba histolytica (IC50 = 32.94 ± 0.27μM), and Naegleria fowleri (44.27 ± 4.02% mortality at 20μM). suggesting a conserved mitochondrial vulnerability across evolutionarily distinct protozoan pathogens. Mitochondrial electron transportdisruption induced membrane depolarization, elevated ROS, γH2AX-associated DNA damage, phospho-p53 (Ser15) activation, G2/M-phase arrest, and caspase-9/-3-dependent apoptosis. Transcriptomic profiling revealed oxidative and proteotoxic stress with suppression of metabolic and translational pathways. Synergism between inhibitors of mitochondrial complexes I and III further supported mitochondrial electron transport as a therapeutically exploitable pathway.\n\nDiscussion: These findings reveal mitochondria‐dependent vulnerabilities as exploitable weaknesses across protozoa. Rotenone, though unsuitable for clinical use due to systemic toxicity, serves as a prototype compound that demonstrates mitochondrial metabolic vulnerability beyond lineage boundaries. By establishing mitochondrial bioenergetics as a resistance‐independent therapeutic node, this work provides a foundation for designing safer, broad‐spectrum antiparasitic agents that selectively exploit mitochondrial pathways.",
  "abstract_shown": true,
  "affiliations": [
    "National Institute of Animal Biotechnology , ,",
    "Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER) , ,",
    "Laboratory of Infectious Diseases, Centre for DNA Fingerprinting and Diagnostics (CDFD) , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Madhusmita Subudhi"
    },
    {
      "affs": [
        1
      ],
      "name": "Siva Singothu"
    },
    {
      "affs": [
        1
      ],
      "name": "Vasundhra Bhandari"
    },
    {
      "affs": [
        1
      ],
      "name": "Umarani Brahma"
    },
    {
      "affs": [
        2
      ],
      "name": "Kuldeep Verma"
    },
    {
      "affs": [
        2
      ],
      "name": "Padavala Navyaka"
    },
    {
      "affs": [
        0
      ],
      "name": "Akash Suresh"
    },
    {
      "affs": [
        0
      ],
      "name": "Sakshi Singh"
    },
    {
      "affs": [
        0
      ],
      "name": "Paresh Sharma"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/545m83np65w1b.bib",
  "cited_by": 0,
  "doi": "10.3389/fcimb.2026.1908136",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13724478/?tool=EBI",
  "id": "545m83np65w1b",
  "issns": [
    "2235-2988"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13724478",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2405|Vector-borne infectious diseases"
    ]
  ],
  "openalex": "W7222919421",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13724478/pdf/?tool=EBI",
  "pmcid": "PMC13724478",
  "pmid": "42973691",
  "published": "2026-10-19",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/545m83np65w1b.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T15:20:50Z",
      "native_id": "PMC:PMC13724478",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13724478"
    },
    {
      "first_seen": "2026-11-04T12:23:02Z",
      "native_id": "PMC13724478",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fcimb.2026.1908136"
    },
    {
      "first_seen": "2026-11-04T15:20:48Z",
      "native_id": "MED:42973691",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42973691"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2405|Vector-borne infectious diseases",
      "subfield": "microbiology"
    }
  ],
  "title": "Complex I inhibition collapses host bioenergetics and activates p53‐dependent apoptosis in Theileria annulata infected cells",
  "title_text": "Complex I inhibition collapses host bioenergetics and activates p53‐dependent apoptosis in Theileria annulata infected cells",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:20:56Z",
  "url": "https://research.draconitic.com/paper/545m83np65w1b",
  "venue": "Frontiers in cellular and infection microbiology",
  "versions": []
}