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Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases


Mitochondria fragmentation destabilizes mitochondrial membranes, promotes oxidative stress and facilitates cell death, thereby contributing to the development and the progression of several mitochondria-related diseases. Accordingly, compounds that reverse mitochondrial fragmentation could have therapeutic potential in treating such diseases. BGP-15, a hydroxylamine derivative, prevents insulin resistance in humans and protects against several oxidative stress-related diseases in animal models. Here we show that BGP-15 promotes mitochondrial fusion by activating optic atrophy 1 (OPA1), a GTPase dynamin protein that assist fusion of the inner mitochondrial membranes. Suppression of Mfn1, Mfn2 or OPA1 prevents BGP-15-induced mitochondrial fusion. BGP-15 activates Akt, S6K, mTOR, ERK1/2 and AS160, and reduces JNK phosphorylation which can contribute to its protective effects. Furthermore, BGP-15 protects lung structure, activates mitochondrial fusion, and stabilizes cristae membranes in vivo determined by electron microscopy in a model of pulmonary arterial hypertension. These data provide the first evidence that a drug promoting mitochondrial fusion in in vitro and in vivo systems can reduce or prevent the progression of mitochondria-related disorders.

Type Journal
ISBN 1873-2968 (Electronic) 0006-2952 (Linking)
Authors Szabo, A.; Sumegi, K.; Fekete, K.; Hocsak, E.; Debreceni, B.; Setalo, G., Jr.; Kovacs, K.; Deres, L.; Kengyel, A.; Kovacs, D.; Mandl, J.; Nyitrai, M.; Febbraio, M. A.; Gallyas, F., Jr.; Sumegi, B.
Responsible Garvan Author (missing name)
Published Date 2018-02-03
Published Volume 150
Published Pages 86-96
Status Published in-print
DOI 10.1016/j.bcp.2018.01.038
URL link to publisher's version
OpenAccess link to author's accepted manuscript version