Mitochondrial KMT9 methylates DLAT to control pyruvate dehydrogenase activity and prostate cancer growth

Yanhan Jia, Sheng Wang, Sylvia Urban, Judith M. Müller, Manuela Sum, Qing Wang, Helena Bauer, Uwe Schulte, Heike Rampelt, Nikolaus Pfanner, Katrin M. Schüle, Axel Imhof, Ignasi Forné, Christopher Berlin, August Sigle, Christian Gratzke, Holger Greschik, Eric Metzger () and Roland Schüle ()
Additional contact information
Yanhan Jia: Klinikum der Universität Freiburg
Sheng Wang: Klinikum der Universität Freiburg
Sylvia Urban: Klinikum der Universität Freiburg
Judith M. Müller: Klinikum der Universität Freiburg
Manuela Sum: Klinikum der Universität Freiburg
Qing Wang: Complete Omics Inc.
Helena Bauer: Klinikum der Universität Freiburg
Uwe Schulte: University of Freiburg
Heike Rampelt: University of Freiburg
Nikolaus Pfanner: University of Freiburg
Katrin M. Schüle: University of Freiburg
Axel Imhof: Ludwig-Maximilians-Universität München
Ignasi Forné: Ludwig-Maximilians-Universität München
Christopher Berlin: University of Freiburg
August Sigle: Klinikum der Universität Freiburg
Christian Gratzke: Klinikum der Universität Freiburg
Holger Greschik: Klinikum der Universität Freiburg
Eric Metzger: Klinikum der Universität Freiburg
Roland Schüle: Klinikum der Universität Freiburg

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Prostate cancer (PCa) growth depends on de novo lipogenesis controlled by the mitochondrial pyruvate dehydrogenase complex (PDC). In this study, we identify lysine methyltransferase (KMT)9 as a regulator of PDC activity. KMT9 is localized in mitochondria of PCa cells, but not in mitochondria of other tumor cell types. Mitochondrial KMT9 regulates PDC activity by monomethylation of its subunit dihydrolipoamide transacetylase (DLAT) at lysine 596. Depletion of KMT9 compromises PDC activity, de novo lipogenesis, and PCa cell proliferation, both in vitro and in a PCa mouse model. Finally, in human patients, levels of mitochondrial KMT9 and DLAT K596me1 correlate with Gleason grade. Together, we present a mechanism of PDC regulation and an example of a histone methyltransferase with nuclear and mitochondrial functions. The dependency of PCa cells on mitochondrial KMT9 allows to develop therapeutic strategies to selectively fight PCa.

Date: 2025
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DOI: 10.1038/s41467-025-56492-8

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