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

A. Szabó, Katalin Sumegi, Katalin Fekete, Eniko Hocsak, B. Debreceni, Gyorgy Setalo, Krisztina Kovacs, Laszlo Deres, Andras Kengyel, Dominika Kovacs, J. Mandl, M. Nyitrai, Mark A. Febbraio, F. Gallyas, B. Sümegi

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)86-96
Number of pages11
JournalBiochemical Pharmacology
Volume150
DOIs
Publication statusPublished - Apr 1 2018

Fingerprint

Mitochondrial Dynamics
Mitochondria
Fusion reactions
Chemical activation
Autosomal Dominant Optic Atrophy
Oxidative stress
Mitochondrial Membranes
Membranes
Optics
Oxidative Stress
Dynamins
Animal Disease Models
Hydroxylamine
Phosphorylation
GTP Phosphohydrolases
Cell death
Pulmonary Hypertension
Electron microscopy
Insulin Resistance
Electron Microscopy

Keywords

  • BGP-15
  • Mitochondrial fragmentation
  • Optic atrophy 1
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases. / Szabó, A.; Sumegi, Katalin; Fekete, Katalin; Hocsak, Eniko; Debreceni, B.; Setalo, Gyorgy; Kovacs, Krisztina; Deres, Laszlo; Kengyel, Andras; Kovacs, Dominika; Mandl, J.; Nyitrai, M.; Febbraio, Mark A.; Gallyas, F.; Sümegi, B.

In: Biochemical Pharmacology, Vol. 150, 01.04.2018, p. 86-96.

Research output: Contribution to journalArticle

Szabó, A. ; Sumegi, Katalin ; Fekete, Katalin ; Hocsak, Eniko ; Debreceni, B. ; Setalo, Gyorgy ; Kovacs, Krisztina ; Deres, Laszlo ; Kengyel, Andras ; Kovacs, Dominika ; Mandl, J. ; Nyitrai, M. ; Febbraio, Mark A. ; Gallyas, F. ; Sümegi, B. / Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases. In: Biochemical Pharmacology. 2018 ; Vol. 150. pp. 86-96.
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