TY - JOUR
T1 - Modulating mitofusins to control mitochondrial function and signaling
AU - Zacharioudakis, Emmanouil
AU - Agianian, Bogos
AU - Kumar MV, Vasantha
AU - Biris, Nikolaos
AU - Garner, Thomas P.
AU - Rabinovich-Nikitin, Inna
AU - Ouchida, Amanda T.
AU - Margulets, Victoria
AU - Nordstrøm, Lars Ulrik
AU - Riley, Joel S.
AU - Dolgalev, Igor
AU - Chen, Yun
AU - Wittig, Andre J.H.
AU - Pekson, Ryan
AU - Mathew, Chris
AU - Wei, Peter
AU - Tsirigos, Aristotelis
AU - Tait, Stephen W.G.
AU - Kirshenbaum, Lorrie A.
AU - Kitsis, Richard N.
AU - Gavathiotis, Evripidis
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.
AB - Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins.
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U2 - 10.1038/s41467-022-31324-1
DO - 10.1038/s41467-022-31324-1
M3 - Article
C2 - 35798717
AN - SCOPUS:85133560745
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3775
ER -