Stanford Advisors

All Publications

  • The MIRO1-BAX Complex Dictates Life and Death at the Mitochondrial Gate. bioRxiv : the preprint server for biology Sainz, A. G., Kwak, C. S., Cho, K. B., Sripadanna, S. A., Bergsneider, B. H., Zizzo, Z., Durairaj, A. S., Du, Z., Cooney, I., Venida, A., Bharucha, N., Karakikes, I., Chiu, W., Lim, M., Bassik, M. C., Wang, X. 2026

    Abstract

    BAX macropores in the outer mitochondrial membrane (OMM) are canonical mediators of apoptosis, but whether the same pore structure can drive distinct cell death pathways remains unclear. Here, we identify the OMM protein MIRO1 as a context-specific modulator of BAX activity. Mechanistically, MIRO1 binds BAX via MIRO1's N-terminal domain to promote macropore formation and the release of mitochondrial DNA (mtDNA) into the cytoplasm, triggering the STING-pIRF3 signaling axis. In glioma cells, this pathway sustains GPX4 expression via pIRF3-mediated transcriptional activation and confers ferroptosis resistance while bypassing inflammation. By contrast, in Parkinsonian neurons, the MIRO1-BAX complex promotes mitochondrial-stress-induced apoptosis. Using structure-guided drug discovery, we developed first-in-class small molecules that allosterically disrupt the MIRO1-BAX complex by engaging MIRO1's distal GTPase pocket. These compounds sensitize glioma cells to ferroptosis and protect neurons from apoptosis. Our findings reveal a disease-specific mitochondrial switch for life-death decisions and illuminate the molecular logic by which cells exploit and interpret OMM permeabilization.

    View details for DOI 10.64898/2026.06.29.733391

    View details for PubMedID 42427686

    View details for PubMedCentralID PMC13345101

  • Chemical modulation of Miro1 alleviates cell-type-specific vulnerabilities in Friedreich's ataxia. Cell chemical biology Chandra, S., Kwak, C. S., Du, Z., Barisano, G., Nguyen, K. T., Vinogradov, V., Wang, X. 2026

    Abstract

    Friedreich's ataxia (FA) is marked by early-onset sensory neurodegeneration and cardiomyopathy. We establish a human dual-cell model of FA by differentiating sensory neurons and cardiomyocytes from the same patients, enabling parallel molecular profiling of disease-relevant cell types. Proteomic analysis reveals distinct, cell-type-specific pathway disruptions in response to frataxin deficiency. Leveraging this platform, we investigate Miro1 reducer 3 (MR3), a selective chemical probe binding Miro1, a mitochondrial outer membrane protein implicated in redox regulation in FA. MR3 treatment modulates molecular signatures in a cell-type-dependent manner, altering pathways related to cardiac contractility in cardiomyocytes and synaptic function in sensory neurons. Mechanistically, MR3 reduces mitochondrial reactive oxygen species and restores membrane potential in FA sensory neurons via potential allosteric reshaping of Miro1 protein. We expand the chemical diversity of this scaffold by conducting ligand-based virtual screening of over 3 billion compounds and identifying previously uncharacterized Miro1 ligands with improved docking and neuroprotective capacity.

    View details for DOI 10.1016/j.chembiol.2026.05.004

    View details for PubMedID 42259290

  • Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering. Nature communications Nakamura, K., Aoyama-Ishiwatari, S., Nagao, T., Paaran, M., Obara, C. J., Sakurai-Saito, Y., Johnston, J., Du, Y., Suga, S., Tsuboi, M., Nakakido, M., Tsumoto, K., Kishi, Y., Gotoh, Y., Kwak, C., Rhee, H. W., Seo, J. K., Kosako, H., Potter, C., Carragher, B., Lippincott-Schwartz, J., Polleux, F., Hirabayashi, Y. 2025; 16 (1): 3401

    Abstract

    Mitochondria-ER membrane contact sites (MERCS) represent a fundamental ultrastructural feature underlying unique biochemistry and physiology in eukaryotic cells. The ER protein PDZD8 is required for the formation of MERCS in many cell types, however, its tethering partner on the outer mitochondrial membrane (OMM) is currently unknown. Here we identify the OMM protein FKBP8 as the tethering partner of PDZD8 using a combination of unbiased proximity proteomics, CRISPR-Cas9 endogenous protein tagging, Cryo-electron tomography, and correlative light-electron microscopy. Single molecule tracking reveals highly dynamic diffusion properties of PDZD8 along the ER membrane with significant pauses and captures at MERCS. Overexpression of FKBP8 is sufficient to narrow the ER-OMM distance, whereas independent versus combined deletions of these two proteins demonstrate their interdependence for MERCS formation. Furthermore, PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner. Our results identify a novel ER-mitochondria tethering complex that regulates mitochondrial morphology in mammalian cells.

    View details for DOI 10.1038/s41467-025-58538-3

    View details for PubMedID 40246839

    View details for PubMedCentralID PMC12006300

  • Human stem cell-specific epigenetic signatures control transgene expression. Biochimica et biophysica acta. Gene regulatory mechanisms Kwak, C. S., Oflaz, F. E., Qiu, J., Wang, X. 2024: 195063

    Abstract

    Human stem cell-derived models have emerged as an important platform to study tissue differentiation and disease mechanisms. Those models could capitalize on biochemical and cell biological methodologies such as omics, autophagy, and organelle dynamics. However, epigenetic silencing in stem cells creates a barrier to apply genetically encoded tools. Here we investigate the molecular mechanisms underlying exogenously expressed gene silencing by employing multiple commonly used promoters in human induced pluripotent stem cells (iPSCs), glioblastoma cells (GBM), and embryonic kidney cells (HEK). We discover that all promoters tested are highly methylated on the CpG island regions with lower protein expression in iPSCs, as compared to non-iPSCs. Elongation factor 1 alpha short (EF1α short or EFS) promoter, which has fewer CpG island number compared to the other promoters, can drive relatively higher gene expression in iPSCs, despite CpG methylation. Adding a minimal A2 ubiquitous chromatin opening element (minimal A2 UCOE or miniUCOE) upstream of a promoter inhibits CpG methylation and enhances gene expression in iPSCs. Our results demonstrate stem cell type-specific epigenetic modification of transgenic promoter region and provide useful information for designing anti-silencing strategies to increase transgene expression in iPSCs.

    View details for DOI 10.1016/j.bbagrm.2024.195063

    View details for PubMedID 39437851

  • Mitochondrial Thermogenesis Can Trigger Heat Shock Response in the Nucleus ACS CENTRAL SCIENCE Kang, M., Kim, H., Lee, H., Kwak, C., Koh, H., Kang, B., Roe, J., Rhee, H. 2024

    View details for DOI 10.1021/acscentsci.3c01589

    View details for Web of Science ID 001238289700001

  • A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease. Cell reports Bharat, V., Durairaj, A. S., Vanhauwaert, R., Li, L., Muir, C. M., Chandra, S., Kwak, C. S., Le Guen, Y., Nandakishore, P., Hsieh, C. H., Rensi, S. E., Altman, R. B., Greicius, M. D., Feng, L., Wang, X. 2023; 42 (12): 113544

    Abstract

    Dysregulated iron or Ca2+ homeostasis has been reported in Parkinson's disease (PD) models. Here, we discover a connection between these two metals at the mitochondria. Elevation of iron levels causes inward mitochondrial Ca2+ overflow, through an interaction of Fe2+ with mitochondrial calcium uniporter (MCU). In PD neurons, iron accumulation-triggered Ca2+ influx across the mitochondrial surface leads to spatially confined Ca2+ elevation at the outer mitochondrial membrane, which is subsequently sensed by Miro1, a Ca2+-binding protein. A Miro1 blood test distinguishes PD patients from controls and responds to drug treatment. Miro1-based drug screens in PD cells discover Food and Drug Administration-approved T-type Ca2+-channel blockers. Human genetic analysis reveals enrichment of rare variants in T-type Ca2+-channel subtypes associated with PD status. Our results identify a molecular mechanism in PD pathophysiology and drug targets and candidates coupled with a convenient stratification method.

    View details for DOI 10.1016/j.celrep.2023.113544

    View details for PubMedID 38060381

  • Split-TurboID enables contact-dependent proximity labeling in cells PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cho, K. F., Branon, T. C., Rajeev, S., Svinkina, T., Udeshi, N. D., Thoudam, T., Kwak, C., Rhee, H., Lee, I., Carr, S. A., Ting, A. Y. 2020; 117 (22): 12143–54

    View details for DOI 10.1073/pnas.1919528117/-/DCSupplemental

    View details for Web of Science ID 000538147800042