Stephanie Herkenne's paper is finally out! Congratulations to Stephanie, another supertalent I had the privilege to mentor, to all our coauthors on Twitter @MargheZamb @AnnaPellattiero @FonsecaBranco @NatasciaTiso @SorianoMageni @GiacoMarta @ElenaEleziv @MarionaGraupera or not 1/ https://twitter.com/Cell_Metabolism/status/1252250051201470464

Thanks to all the funding agencies that made this possible: this paper is the result of 6 years of intense work by Stephanie and many others, and of a 10 years long research program: @AIRC_it @Fondaz_Veronesi @ERC_Research @MiurSocial @DiBio_UniPD @FRBiomedica @Telethonitalia 2/

Because we believe that this is a very important story, we prepared a Tweetorial you might read in between Zoom/Skype/Facetime/Whatsapp meetings.
Stephanie came to the lab with a clear question: what is the role of mitochondrial dynamics in angiogenesis? 3/

She found early and remarkable mitochondrial elongation in angiogenesis in D. rerio with @NatasciaTiso, F. Argenton, in mouse and in HUVEC. Mining public RNAseq data with G. Sales of @DiBio_UniPD they discovered a signature of mitochondrial activation in stimulated HUVEC 4/

Among the mitochondrial fusion/fission genes, only Opa1 was upregulated early. Stephanie indeed proved Opa1 upregulation is essential for angiogenesis. A key experiment here was to engineer a mouse where genomic Opa1 was excised yet Opa1 was expressed transgenically 5/

Using endothelial cells from this mouse, Stephanie showed that pro-angiogenic factors like VEGF can't induce angiogenesis if they do not upregulate Opa1 transcription. Very often we read "gene X controls process Y" because we knock X out and Y is affected. 6/

Such experiments just tell that if you knock X out, you somehow affect process Y. Here using a complex strategy Stephanie formally and genetically proved that *induction* of Opa1 is required for angiogenesis. Other fusion genes Mfn1 and 2 are dispensable. How does Opa1 work? 7/

Fusion? cristae shape? ATP production? Surprise: it's all about MICU1 and calcium! Opa1 controls MICU1 association with MCU, hence Ca2+ levels and ultimately IKBa degradation, NFkB activation and timely transcription of proangiogenic genes. 8/

Because of the strong impact of Opa1 deletion on angiogenesis, Stephanie wanted to test if endothelial Opa1 deletion impacts on tumor growth and metastatization. It does, on 2 different models of tumor growth and 3 of tumor metastatization in a gene dose dependent manner. 9/

We therefore used a first in kind drug @AnnaPellattiero, C. Quirin developed in the lab with @ProfGavathiotis: MYLS22, a selective Opa1 inhibitor. Stay tuned to see how we discovered and characterized it. MYLS22 is promising in other cancers, right @glytsou @iannisaifantis1? 10/

MYLS22 reduced tumor growth by ~80%, depending on endothelial Opa1, without causing side effects.
The paper goes from process discovery to mechanism to its selective drugging. It contains much more than this, so please read it! Thanks @Cell_Metabolism for tweeting about it!-LS