Adaptative Capacity of Mitochondrial Biogenesis and of Mitochondrial Dynamics in Response to Pathogenic Respiratory Chain Dysfunction
Antioxidants & Redox Signaling. 2013-08-01; 19(4): 350-365
DOI: 10.1089/ARS.2011.4244
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1. Antioxid Redox Signal. 2013 Aug 1;19(4):350-65. doi: 10.1089/ars.2011.4244. Epub
2012 Apr 19.
Adaptative capacity of mitochondrial biogenesis and of mitochondrial dynamics in
response to pathogenic respiratory chain dysfunction.
Benard G(1), Trian T, Bellance N, Berger P, Lavie J, Espil-Taris C, Rocher C,
Eimer-Bouillot S, Goizet C, Nouette-Gaulain K, Letellier T, Lacombe D, Rossignol
R.
Author information:
(1)Université Bordeaux, Maladies Rares: Génétique et Métabolisme (MRGM), EA 4576,
F-33000 Bordeaux, France.
AIMS: 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.
INNOVATION: 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.
DOI: 10.1089/ars.2011.4244
PMID: 22369111 [Indexed for MEDLINE]