Phase1 may demonstrate target engagement, page-17

All this research about mitochondrion fusion, fission, p53, mdivi-1, drp1, cell death and prevention of cell death is interesting. It makes you wonder what happens if you add in here a new molecule, PBT434 and in fact Prana should know it. But PBT434 is not the first drug dealing with these mitochondrial molecules, we have only not known that these drugs work on this level. How angiotensin II receptor blocking works is a good example. See below the free article. It tells why the heart cells do not die when you treat hypertension by blocking angiotensin II receptors. As you may remember this same drug seems to prevent also Alzheimer's, so it prevents dying of brain cells, too. So it is very likely that PBT434 also could block dying of some other cells, not only that of brain cells.

Front Pharmacol. 2018 Mar 9;9:176. doi: 10.3389/fphar.2018.00176. eCollection 2018.
Mitochondrial Fission Is Required for Angiotensin II-Induced Cardiomyocyte Apoptosis Mediated by a Sirt1-p53 Signaling Pathway.

Qi J^1,2, Wang F³, Yang P¹, Wang X², Xu R¹, Chen J¹, Yuan Y⁴, Lu Z^1,2, Duan J².
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Abstract

Hypertension-induced cardiac apoptosis is a major contributor to early-stage heart-failure. Our previous studies have found that p53-mediated mitochondrial fission is involved in aldosterone-induced podocyte apoptosis. However, it is not clear that whether p53-induced mitochondrial fission is critical for hypertensive Angiotensin II (AngII)-induced cardiomyocyte apoptosis. In this study, we found that inhibition of the mitochondrial fission protein Drp1 (dynamin-related protein 1) by Mdivi-1 prevented cardiomyocyte apoptosis and cardiac remodeling in SHRs. In vitro we found that treatment of cultured neonatal rat cardiomyocytes with AngII induced Drp1 expression, mitochondrial fission, and apoptosis. Knockdown of Drp1 inhibited AngII-induced mitochondrial fission and cardiomyocyte apoptosis. Furthermore, AngII induced p53 acetylation. Knockdown of p53 inhibited AngII-induced Drp1 expression, mitochondrial fission, and cardiomyocyte apoptosis. Besides, we found that Sirt1 was able to reverse AngII-induced p53 acetylation and its binding to the Drp1 promoter, which subsequently inhibited mitochondrial fission and eventually attenuated cardiomyocyte apoptosis. Collectively, these results suggest that AngII degrades Sirt1 to increase p53 acetylation, which induces Drp1 expression and eventually results in cardiomyocyte apoptosis. Sirt1/p53/Drp1dependent mitochondrial fission may be a valuable therapeutic target for hypertension induced heart failure.​