Stress-induced OMA1 activation and autocatalytic turnover regulate OPA1-dependent mitochondrial dynamics

The dynamic network of mitochondria fragments under stress allowing the segregation of damaged mitochondria and, in case of persistent damage, their selective removal by mitophagy. Mitochondrial fragmentation upon depolarisation of mitochondria is brought about by the degradation of central componen...

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Bibliographic Details
Published in:	The EMBO journal 2014-03, Vol.33 (6), p.578-593
Main Authors:	Baker, Michael J, Lampe, Philipp A, Stojanovski, Diana, Korwitz, Anne, Anand, Ruchika, Tatsuta, Takashi, Langer, Thomas
Format:	Article
Language:	eng
Subjects:	Animals Cellular biology Centrifugation, Density Gradient Electrophoresis, Polyacrylamide Gel Enzyme Activation - physiology Fibroblasts GTP Phosphohydrolases - metabolism Immunoblotting Metalloproteases - genetics Metalloproteases - metabolism Mice Mice, Knockout Microscopy, Fluorescence Mitochondria Mitochondrial Dynamics - physiology mitochondrial fusion Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Models, Biological OMA1 OPA1 Proteases stress Stress, Physiological - physiology
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Summary:	The dynamic network of mitochondria fragments under stress allowing the segregation of damaged mitochondria and, in case of persistent damage, their selective removal by mitophagy. Mitochondrial fragmentation upon depolarisation of mitochondria is brought about by the degradation of central components of the mitochondrial fusion machinery. The OMA1 peptidase mediates the degradation of long isoforms of the dynamin‐like GTPase OPA1 in the inner membrane. Here, we demonstrate that OMA1‐mediated degradation of OPA1 is a general cellular stress response. OMA1 is constitutively active but displays strongly enhanced activity in response to various stress insults. We identify an amino terminal stress‐sensor domain of OMA1, which is only present in homologues of higher eukaryotes and which modulates OMA1 proteolysis and activation. OMA1 activation is associated with its autocatalyic degradation, which initiates from both termini of OMA1 and results in complete OMA1 turnover. Autocatalytic proteolysis of OMA1 ensures the reversibility of the response and allows OPA1‐mediated mitochondrial fusion to resume upon alleviation of stress. This differentiated stress response maintains the functional integrity of mitochondria and contributes to cell survival. Synopsis A sensor domain for mitochondrial stress and a novel self‐degradation mechanism enables the mitochondrial protease OMA1 to reversibly control mitochondrial fragmentation in response to various cellular stresses. Various cellular stress conditions activate OMA1 and induce OPA1 processing and mitochondrial fragmentation. A stress‐sensor domain is present outside the conserved metallopeptidase domain in the amino terminal region of mammalian OMA1. OMA1 activation is accompanied by its autocatalytic turnover ensuring the reversibility of the response. A sensor domain for mitochondrial stress and a novel self‐degradation mechanism enables the mitochondrial protease OMA1 to reversibly control mitochondrial fragmentation in response to various cellular stresses.
ISSN:	0261-4189 1460-2075