TRPML1 loss disrupts lysosome–mitochondria homeostasis and sensitizes MDA-MB-231 triple-negative breast cancer cells to chemotherapy
7 affiliations
- 1Department of Physiology and Biophysics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
- 2Graduate Program in Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
- 3Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- 4Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- 5UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- 6Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
- 7Department of Biochemistry and Molecular Biology, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada
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.
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BibTeX
@article{syeda2026trpml1,
title = {{TRPML1 loss disrupts lysosome–mitochondria homeostasis and sensitizes MDA-MB-231 triple-negative breast cancer cells to chemotherapy}},
author = {Alia K.R. Syeda and Shekoufeh Almasi and Cory J. Benson and Barry E. Kennedy and Ryan M. Yoast and Scott M. Emrich and Amari Delima-Baril and Logan Slade and Shanmugasundaram Pakkiriswami and Vishnu V. Vijayan and Unnikrishnan B. Sheela and Shashi Gujar and Thomas Pulinilkunnil and Mohamed Trebak and Yassine El Hiani},
journal = {The Journal of Biological Chemistry},
year = {2026},
month = sep,
doi = {10.1016/j.jbc.2026.113596},
url = {https://doi.org/10.1016/j.jbc.2026.113596},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - TRPML1 loss disrupts lysosome–mitochondria homeostasis and sensitizes MDA-MB-231 triple-negative breast cancer cells to chemotherapy
AU - Alia K.R. Syeda
AU - Shekoufeh Almasi
AU - Cory J. Benson
AU - Barry E. Kennedy
AU - Ryan M. Yoast
AU - Scott M. Emrich
AU - Amari Delima-Baril
AU - Logan Slade
AU - Shanmugasundaram Pakkiriswami
AU - Vishnu V. Vijayan
AU - Unnikrishnan B. Sheela
AU - Shashi Gujar
AU - Thomas Pulinilkunnil
AU - Mohamed Trebak
AU - Yassine El Hiani
PY - 2026
DA - 2026/09/23
JO - The Journal of Biological Chemistry
DO - 10.1016/j.jbc.2026.113596
UR - https://doi.org/10.1016/j.jbc.2026.113596
AB - 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.
SN - 0021-9258
SN - 1083-351X
ER -