Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1
| Autor: | Thomas Langer, Giuseppe Mancuso, Benedikt Westermann, Jean-Claude Martinou, Ines Raschke, Sarah Ehses, Stefan Geimer, Andrea Bernacchia, Daniel Tondera, Elena I. Rugarli |
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| Rok vydání: | 2009 |
| Předmět: |
endocrine system
Isoenzymes/genetics/metabolism/physiology Mitochondrion Biology Article GTP Phosphohydrolases Mitochondrial Proteins Mice ATP-Dependent Proteases ddc:570 Metalloendopeptidases/genetics/metabolism/physiology Mitochondrial inner membrane fusion Mitochondria/metabolism Enzyme Stability medicine Animals Humans Inner mitochondrial membrane GTP Phosphohydrolases/genetics/metabolism Cells Cultured Research Articles Adenosine Triphosphatases Paraplegin Metalloendopeptidases Adenosine Triphosphatases/metabolism Cell Biology medicine.disease Mitochondrial carrier eye diseases Mitochondria Isoenzymes Biochemistry mitochondrial fusion Metalloproteases ATPases Associated with Diverse Cellular Activities Optic Atrophy 1 RNA Interference ATP–ADP translocase |
| Zdroj: | J Cell Biol The Journal of Cell Biology The Journal of Cell Biology, Vol. 187, No 7 (2009) pp. 1023-36 |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.200906084 |
| Popis: | m-AAA proteases cleave OPA1 to ensure a balance of long and short OPA1 isoforms, whereas cleavage by OMA1 causes an accumulation of the short OPA1 variants. (See also companion paper from Head et al. in this issue.) Mitochondrial fusion depends on the dynamin-like guanosine triphosphatase OPA1, whose activity is controlled by proteolytic cleavage. Dysfunction of mitochondria induces OPA1 processing and results in mitochondrial fragmentation, allowing the selective removal of damaged mitochondria. In this study, we demonstrate that two classes of metallopeptidases regulate OPA1 cleavage in the mitochondrial inner membrane: isoenzymes of the adenosine triphosphate (ATP)–dependent matrix AAA (ATPase associated with diverse cellular activities [m-AAA]) protease, variable assemblies of the conserved subunits paraplegin, AFG3L1 and -2, and the ATP-independent peptidase OMA1. Functionally redundant isoenzymes of the m-AAA protease ensure the balanced accumulation of long and short isoforms of OPA1 required for mitochondrial fusion. The loss of AFG3L2 in mouse tissues, down-regulation of AFG3L1 and -2 in mouse embryonic fibroblasts, or the expression of a dominant-negative AFG3L2 variant in human cells decreases the stability of long OPA1 isoforms and induces OPA1 processing by OMA1. Moreover, cleavage by OMA1 causes the accumulation of short OPA1 variants if mitochondrial DNA is depleted or mitochondrial activities are impaired. Our findings link distinct peptidases to constitutive and induced OPA1 processing and shed new light on the pathogenesis of neurodegenerative disorders associated with mutations in m-AAA protease subunits. |
| Databáze: | OpenAIRE |
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