title: Adaptative capacity of mitochondrial biogenesis and of mitochondrial dynamics in response to pathogenic respiratory chain dysfunction.
abstract: OBJECTIVE
  Cellular energy homeostasy relies on mitochondrial plasticity, the molecular determinants of which are multiple. Yet, the relative contribution of and possible cooperation between mitochondrial biogenesis and morphogenesis to cellular energy homeostasy remains elusive. Here we analyzed the adaptative capacity of mitochondrial content and dynamics in muscle biopsies of patients with a complex IV defect, and in skin fibroblasts challenged with complex IV inhibition.
  
  
  RESULTS
  We observed a biphasic variation of the mitochondrial content upon complex IV inhibition in muscle biopsies and in skin fibroblasts. Adjustment of mitochondrial content for respiratory maintenance was blocked by using a dominant negative form of CREB (CREB-M1) and by L-NAME, a blocker of NO production. Accordingly, cells treated with KCN 6 μM showed higher levels of phospho-CREB, PGC1α mRNA, eNOS mRNA, and mtTFA mRNA. We also observed the increased expression of the fission protein DRP1 during fibroblasts adaptation, as well as mitochondrial ultrastructural defects indicative of increased fission in patients muscle micrographs. Accordingly, the expression of a dominant negative form of DRP1 (K38A mutant) reduced the biogenic response in fibroblasts challenged with 6 μM KCN.
  
  
  METHODS
  Our findings indicate that mitochondrial biogenesis and mitochondrial fission cooperate to promote cellular adaptation to respiratory chain inhibition.
  
  
  CONCLUSIONS
  Our data show for the first time that DRP1 intervenes during the initiation of the mitochondrial adaptative response to respiratory chain defects. The evidenced pathway of mitochondrial adaptation to respiratory chain deficiency provides a safety mechanism against mitochondrial dysfunction.
authors.affiliation: Université Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576, F-33000 Bordeaux, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Benard
authors.forename: Thomas
authors.initials: T
authors.lastname: Trian
authors.forename: Nadège
authors.initials: N
authors.lastname: Bellance
authors.forename: Patrick
authors.initials: P
authors.lastname: Berger
authors.forename: Julie
authors.initials: J
authors.lastname: Lavie
authors.forename: Caroline
authors.initials: C
authors.lastname: Espil-Taris
authors.forename: Christophe
authors.initials: C
authors.lastname: Rocher
authors.forename: Sandrine
authors.initials: S
authors.lastname: Eimer-Bouillot
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Karine
authors.initials: K
authors.lastname: Nouette-Gaulain
authors.forename: Thierry
authors.initials: T
authors.lastname: Letellier
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Rossignol
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D004579:Electron Transport / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D063154:Mitochondrial Dynamics / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D011190:Potassium Cyanide / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D011190:Potassium Cyanide