Contact

  • Academic
    jimzhang@stanford.edu
    University - Student Department: Department of Structural Biology Position: Graduate

Additional Info

All Publications

  • TMEM65 functions as the mitochondrial Na+/Ca2+ exchanger. Nature cell biology Zhang, J. L., Chang, Y. C., Lai, P. H., Yeh, H. I., Tsai, C. W., Huang, Y. L., Liu, T. Y., Lee, I. C., Foulon, N., Xu, Y., Rao, B., Shih, H. M., Tu, Y. C., Reyes, A. V., Xu, S. L., Feng, L., Tsai, M. F. 2025

    Abstract

    Mitochondria export Ca2+ via Na+/Ca2+ exchange machinery (mito-NCX) to regulate intracellular Ca2+ signalling and mitochondrial Ca2+ homeostasis. TMEM65 has recently been implicated as essential for mito-NCX, but its mechanisms and roles remain unclear. Here we show that TMEM65 depletion severely impairs mito-NCX. TMEM65 is highly expressed in the heart and brain but absent in the liver, correlating with mito-NCX activity in these tissues. Biochemical and functional analyses reveal that TMEM65 forms a homodimer, containing plausible ion-coordinating residues critical for function. Heterologous expression of TMEM65 induces Na+/Ca2+ exchange in cells lacking native mito-NCX activity. Moreover, purified, liposome-reconstituted TMEM65 exhibits key mito-NCX features. We further identify the binding site for CGP-37157, a potent, widely used mito-NCX inhibitor. Finally, TMEM65 deletion elevates mitochondrial Ca2+ and primes mitochondria to permeability transition. These findings firmly establish TMEM65 as the protein mediating mito-NCX, offering a new therapeutic target for diseases associated with mitochondrial Ca2+ dysregulation.

    View details for DOI 10.1038/s41556-025-01721-x

    View details for PubMedID 40691517

    View details for PubMedCentralID 6715724

https://orcid.org/0000-0003-3748-4603