{
  "abstract": "Signaling mechanisms at the lysosome–mitochondria interface form a critical network that enables cancer cells to maintain mitochondrial quality control, adapt to metabolic stress, and survive therapy. However, the incomplete understanding of the mechanisms coordinating this network has limited the development of effective therapies, especially for triple-negative breast cancers (TNBC). Here, we identify TRPML1 as an important regulator of lysosome-mitochondrial communication in MDA-MB-231 TNBC cells. We find that TRPML1 knockdown (ML1-KD) impaired mitochondrial respiration, oxidative substrate utilization, ATP production and redox balance in MDA-MB-231 cells, whereas comparable changes were not observed in non-cancerous MCF10A cells. ML1-KD reduced lysosomal acidification and impaired autophagic flux and was accompanied by reduced TFEB nuclear localization, impaired mitophagy, and alterations in mitochondrial maintenance proteins. These changes were accompanied by organellar proximity remodeling, with increased mitochondria–ER proximity and reduced mitochondria-lysosome proximity, together with altered cytosolic/mitochondrial Ca2+ responses, broad metabolic remodeling, G0/G1 arrest, and caspase-3/7-independent cell death. Importantly, ML1-KD cells showed enhanced responses to otherwise subeffective concentrations of doxorubicin and paclitaxel. Together, our findings support TRPML1-dependent lysosomal signaling as an important contributor to mitochondrial-metabolic resilience and chemotherapy responsiveness in MDA-MB-231 TNBC cells.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada",
    "Graduate Program in Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA",
    "Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA",
    "Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA",
    "UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA",
    "Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada",
    "Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Alia K.R. Syeda"
    },
    {
      "affs": [
        0
      ],
      "name": "Shekoufeh Almasi"
    },
    {
      "affs": [
        1,
        2,
        3,
        4
      ],
      "name": "Cory J. Benson"
    },
    {
      "affs": [
        5
      ],
      "name": "Barry E. Kennedy"
    },
    {
      "affs": [
        1
      ],
      "name": "Ryan M. Yoast"
    },
    {
      "affs": [
        1
      ],
      "name": "Scott M. Emrich"
    },
    {
      "affs": [
        0
      ],
      "name": "Amari Delima-Baril"
    },
    {
      "affs": [
        6
      ],
      "name": "Logan Slade"
    },
    {
      "affs": [
        6
      ],
      "name": "Shanmugasundaram Pakkiriswami"
    },
    {
      "affs": [
        5
      ],
      "name": "Vishnu V. Vijayan"
    },
    {
      "affs": [
        5
      ],
      "name": "Unnikrishnan B. Sheela"
    },
    {
      "affs": [
        5
      ],
      "name": "Shashi Gujar"
    },
    {
      "affs": [
        6
      ],
      "name": "Thomas Pulinilkunnil"
    },
    {
      "affs": [
        1,
        2,
        3,
        4
      ],
      "name": "Mohamed Trebak"
    },
    {
      "affs": [
        0
      ],
      "name": "Yassine El Hiani"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e19m6jre09p3z.bib",
  "cited_by": 3,
  "doi": "10.1016/j.jbc.2026.113596",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13734889/",
  "id": "e19m6jre09p3z",
  "issns": [
    "0021-9258",
    "1083-351X"
  ],
  "landing_url": "https://doi.org/10.1016/j.jbc.2026.113596",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "1314|Calcium signaling and nucleotide metabolism"
    ]
  ],
  "openalex": "W7214061843",
  "pdf_url": null,
  "pmcid": "PMC13734889",
  "pmid": "42772563",
  "published": "2026-09-23",
  "publisher": "American Society for Biochemistry and Molecular Biology",
  "ris": "https://research.draconitic.com/paper/e19m6jre09p3z.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:20:41Z",
      "native_id": "PMC13734889",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.jbc.2026.113596"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1314|Calcium signaling and nucleotide metabolism",
      "subfield": "physiology"
    }
  ],
  "title": "TRPML1 loss disrupts lysosome–mitochondria homeostasis and sensitizes MDA-MB-231 triple-negative breast cancer cells to chemotherapy",
  "title_text": "TRPML1 loss disrupts lysosome–mitochondria homeostasis and sensitizes MDA-MB-231 triple-negative breast cancer cells to chemotherapy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:20:41Z",
  "url": "https://research.draconitic.com/paper/e19m6jre09p3z",
  "venue": "The Journal of Biological Chemistry",
  "versions": []
}