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


Szabo, Aliz; Sumegi, Katalin; Fekete, Katalin; Hocsak, Eniko; Debreceni, Balazs; Setalo, Gyorgy; Kovacs, Krisztina; Deres, Laszlo; Kengyel, Andras; Kovacs, Dominika; Mandl, Jozsef; Nyitrai, Miklos; Febbraio, Mark A; Gallyas, Ferenc; Sumegi, Balazs

Publication Year 2018
Journal Biochemical Pharmacology
Pages 86-96
Volume 150
PMID 29378182.0
DOI 10.1016/j.bcp.2018.01.038

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. Copyright ? 2018 The Author(s). Published by Elsevier Inc. All rights reserved.