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 - Funding Information:
We thank David Chan for providing MEF cell lines. Studies were supported by NIH grants P01AG031782, R01CA178394, and the Irma T. Hirschl Trust Career Award to E.G., R01HL138475, and Fondation Leducq (RA15CVD04) to R.N.K. L.A.K. is supported by a Foundation Grant by the Canadian Institute for Health Research (CIHR), L.A.K. is a Canada Research Chair in Molecular Cariology, I.R.N. holds a CIHR post-doctoral fellowship award. NMR, chemistry, and imaging resources are supported from NIH grants 1S10OD016305 and P30 CA013330. Cartoons in Fig. were created with Biorender.com.
Funding Information:
We thank David Chan for providing MEF cell lines. Studies were supported by NIH grants P01AG031782, R01CA178394, and the Irma T. Hirschl Trust Career Award to E.G., R01HL138475, and Fondation Leducq (RA15CVD04) to R.N.K. L.A.K. is supported by a Foundation Grant by the Canadian Institute for Health Research (CIHR), L.A.K. is a Canada Research Chair in Molecular Cariology, I.R.N. holds a CIHR post-doctoral fellowship award. NMR, chemistry, and imaging resources are supported from NIH grants 1S10OD016305 and P30 CA013330. Cartoons in Fig. 8 were created with Biorender.com.
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.
UR - http://www.scopus.com/inward/record.url?scp=85133560745&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133560745&partnerID=8YFLogxK
U2 - 10.1038/s41467-022-31324-1
DO - 10.1038/s41467-022-31324-1
M3 - Article
C2 - 35798717
AN - SCOPUS:85133560745
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3775
ER -