Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1
Sarah Ehses,Ines Raschke,Giuseppe Mancuso,Andrea Bernacchia,Stefan Geimer,Daniel Tondera,Jean-Claude Martinou,Benedikt Westermann,Elena I. Rugarli,Thomas Langer,Thomas Langer +10 more
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TLDR
The cleavage by OMA1 causes an accumulation of the short OPA1 variants, and the role ofm-AAA proteases in ensuring a balance of long and short Opa1 isoforms is investigated.Abstract:
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.read more
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References
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OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion
Christian Frezza,Sara Cipolat,Olga Martins de Brito,Massimo Micaroni,Galina V. Beznoussenko,Tomasz Rudka,Davide Bartoli,Roman S. Polishuck,Nika N. Danial,Bart De Strooper,Luca Scorrano +10 more
TL;DR: Evidence is provided that Optic Atrophy 1 (OPA1), a profusion dynamin-related protein of the inner mitochondrial membrane mutated in dominant optic atrophy, protects from apoptosis by preventing cytochrome c release independently from mitochondrial fusion.
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Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis
Aurélien Olichon,Laurent Baricault,Nicole Gas,Emmanuelle Guillou,Annie Valette,Pascale Belenguer,Guy Lenaers +6 more
TL;DR: It is suggested that OPA1 is a major organizer of the mitochondrial inner membrane from which the maintenance of the cristae integrity depends and that abnormal apoptosis is a possible pathophysiological process leading to the retinal ganglion cells degeneration in ADOA patients.
Journal ArticleDOI
Regulation of mitochondrial morphology through proteolytic cleavage of OPA1.
TL;DR: M mammalian mitochondrial function and morphology is regulated through processing of OPA1 in a ΔΨ‐dependent manner through proteolytic cleavage of Mgm1, the yeast homolog of O PA1.
Journal ArticleDOI
Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease
Giorgio Casari,Maurizio De Fusco,Sonia Ciarmatori,Massimo Zeviani,Marina Mora,Patricio Fernandez,Giuseppe De Michele,Alessandro Filla,Sergio Cocozza,Roberto Marconi,Alexandre Dürr,Bertrand Fontaine,Andrea Ballabio +12 more
TL;DR: Analysis of muscle biopsies from two patients carrying Paraplegin mutations showed typical signs of mitochondrial OXPHOS defects, thus suggesting a mechanism for neurodegeneration in HSP-type disorders.
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The Machines that Divide and Fuse Mitochondria
TL;DR: This review focuses on what is currently known about the novel molecular machines that divide and fuse mitochondria, which are derived from eubacteria.