title: Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 signaling pathway.
abstract: Insulin regulates heart metabolism through the regulation of insulin-stimulated glucose uptake. Studies have indicated that insulin can also regulate mitochondrial function. Relevant to this idea, mitochondrial function is impaired in diabetic individuals. Furthermore, the expression of Opa-1 and mitofusins, proteins of the mitochondrial fusion machinery, is dramatically altered in obese and insulin-resistant patients. Given the role of insulin in the control of cardiac energetics, the goal of this study was to investigate whether insulin affects mitochondrial dynamics in cardiomyocytes. Confocal microscopy and the mitochondrial dye MitoTracker Green were used to obtain three-dimensional images of the mitochondrial network in cardiomyocytes and L6 skeletal muscle cells in culture. Three hours of insulin treatment increased Opa-1 protein levels, promoted mitochondrial fusion, increased mitochondrial membrane potential, and elevated both intracellular ATP levels and oxygen consumption in cardiomyocytes in vitro and in vivo. Consequently, the silencing of Opa-1 or Mfn2 prevented all the metabolic effects triggered by insulin. We also provide evidence indicating that insulin increases mitochondrial function in cardiomyocytes through the Akt-mTOR-NFκB signaling pathway. These data demonstrate for the first time in our knowledge that insulin acutely regulates mitochondrial metabolism in cardiomyocytes through a mechanism that depends on increased mitochondrial fusion, Opa-1, and the Akt-mTOR-NFκB pathway.
authors.affiliation: Advanced Center for Chronic Diseases (ACCDIS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Valentina
authors.initials: V
authors.lastname: Parra
authors.forename: Hugo E
authors.initials: HE
authors.lastname: Verdejo
authors.forename: Myriam
authors.initials: M
authors.lastname: Iglewski
authors.forename: Andrea
authors.initials: A
authors.lastname: Del Campo
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Troncoso
authors.forename: Deborah
authors.initials: D
authors.lastname: Jones
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jovan
authors.initials: J
authors.lastname: Kuzmicic
authors.forename: Christian
authors.initials: C
authors.lastname: Pennanen
authors.forename: Camila
authors.initials: C
authors.lastname: Lopez-Crisosto
authors.forename: Fabián
authors.initials: F
authors.lastname: Jaña
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferreira
authors.forename: Eduard
authors.initials: E
authors.lastname: Noguera
authors.forename: Mario
authors.initials: M
authors.lastname: Chiong
authors.forename: David A
authors.initials: DA
authors.lastname: Bernlohr
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.forename: Evan Dale
authors.initials: ED
authors.lastname: Abel
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.forename: Sergio
authors.initials: S
authors.lastname: Lavandero
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D020558:GTP Phosphohydrolases / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000502:physiology*; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D007328:Insulin; D016328:NF-kappa B; C546845:mTOR protein, rat; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020558:GTP Phosphohydrolases; C498811:Opa1 protein, rat