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

• Published in: Biochemical pharmacology Vol. 150; pp. 86 - 96
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.04.2018
• Subjects: A549 Cells; Animals; BGP-15; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; HeLa Cells; Humans; Male; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Diseases - drug therapy; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; Mitochondrial Dynamics - drug effects; Mitochondrial Dynamics - physiology; Mitochondrial fragmentation; Optic atrophy 1; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; Oximes - pharmacology; Oximes - therapeutic use; Piperidines - pharmacology; Piperidines - therapeutic use; Rats; Rats, Wistar; Treatment Outcome; Oxidative stress; BGP-15; Optic atrophy 1; Mitochondrial fragmentation
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2018.01.038

[Display omitted] 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.