title: Early exposure to general anesthesia disturbs mitochondrial fission and fusion in the developing rat brain.
abstract: BACKGROUND
  General anesthetics induce apoptotic neurodegeneration in the developing mammalian brain. General anesthesia (GA) also causes significant disturbances in mitochondrial morphogenesis during intense synaptogenesis. Mitochondria are dynamic organelles that undergo remodeling via fusion and fission. The fine balance between these two opposing processes determines mitochondrial morphometric properties, allowing for their regeneration and enabling normal functioning. As mitochondria are exquisitely sensitive to anesthesia-induced damage, we examined how GA affects mitochondrial fusion/fission.
  
  
  METHODS
  Seven-day-old rat pups received anesthesia containing a sedative dose of midazolam followed by a combined nitrous oxide and isoflurane anesthesia for 6 h.
  
  
  RESULTS
  GA causes 30% upregulation of reactive oxygen species (n = 3-5 pups/group), accompanied by a 2-fold downregulation of an important scavenging enzyme, superoxide dismutase (n = 6 pups/group). Reactive oxygen species upregulation is associated with impaired mitochondrial fission/fusion balance, leading to excessive mitochondrial fission. The imbalance between fission and fusion is due to acute sequestration of the main fission protein, dynamin-related protein 1, from the cytoplasm to mitochondria, and its oligomerization on the outer mitochondrial membrane. These are necessary steps in the formation of the ring-like structures that are required for mitochondrial fission. The fission is further promoted by GA-induced 40% downregulation of cytosolic mitofusin-2, a protein necessary for maintaining the opposing process, mitochondrial fusion (n = 6 pups/group).
  
  
  CONCLUSIONS
  Early exposure to GA causes acute reactive oxygen species upregulation and disturbs the fine balance between mitochondrial fission and fusion, leading to excessive fission and disturbed mitochondrial morphogenesis. These effects may play a causal role in GA-induced developmental neuroapoptosis.
authors: Department of Anesthesiology, University of Virginia Heath System, Charlottesville, VA, USA.
authors: Annalisa
authors: A
authors: Boscolo
authors: Desanka
authors: D
authors: Milanovic
authors: John A
authors: JA
authors: Starr
authors: Victoria
authors: V
authors: Sanchez
authors: Azra
authors: A
authors: Oklopcic
authors: Laurie
authors: L
authors: Moy
authors: Carlo
authors: C
authors: Ori C
authors: Alev
authors: A
authors: Erisir
authors: Vesna
authors: V
authors: Jevtovic-Todorovic
mesh_terms: D000768:Anesthesia, General / Q000009:adverse effects*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D034281:Dynamins / Q000096:biosynthesis / Q000235:genetics; D020558:GTP Phosphohydrolases; D006706:Homeostasis / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D002374:Catalase; D013482:Superoxide Dismutase; D020558:GTP Phosphohydrolases; C489710:Mfn2 protein, rat; C519851:Dnm1l protein, rat; D034281:Dynamins