TY - JOUR
T1 - Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases
AU - Szabo, Aliz
AU - Sumegi, Katalin
AU - Fekete, Katalin
AU - Hocsak, Eniko
AU - Debreceni, Balazs
AU - Setalo, Gyorgy
AU - Kovacs, Krisztina
AU - Deres, Laszlo
AU - Kengyel, Andras
AU - Kovacs, Dominika
AU - Mandl, Jozsef
AU - Nyitrai, Miklos
AU - Febbraio, Mark A.
AU - Gallyas, Ferenc
AU - Sumegi, Balazs
PY - 2018/4/1
Y1 - 2018/4/1
N2 - 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.
AB - 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.
KW - BGP-15
KW - Mitochondrial fragmentation
KW - Optic atrophy 1
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=85041403816&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2018.01.038
DO - 10.1016/j.bcp.2018.01.038
M3 - Article
C2 - 29378182
AN - SCOPUS:85041403816
SN - 0006-2952
VL - 150
SP - 86
EP - 96
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
ER -