The Mitochondrial Protease AFG3L2 Is Essential for Axonal Development

The mitochondrial metalloprotease AFG3L2 assembles with the homologous protein paraplegin to form a supracomplex in charge of the essential protein quality control within mitochondria. Mutations of paraplegin cause a specific axonal degeneration of the upper motoneuron and, therefore, hereditary spastic paraplegia. Here we present two Afg3l2 murine models: a newly developed null and a spontaneous mutant that we found carrier of a missense mutation. Contrasting with the mild and late onset axonal degeneration of paraplegin-deficient mouse, Afg3l2 models display a marked impairment of axonal development with delayed myelination and poor axonal radial growth leading to lethality at P16. The increased severity of the Afg3l2 mutants is explained by two main molecular features that differentiate AFG3L2 from paraplegin: its higher neuronal expression and its versatile ability to support both hetero-oligomerization and homo-oligomerization. Our data assign to AFG3L2 a crucial role by linking mitochondrial metabolism and axonal development. Moreover, we propose AFG3L2 as an excellent candidate for motoneuron and cerebellar diseases with early onset unknown etiology.

[1]  I. Reynolds,et al.  Mitochondrial trafficking and morphology in healthy and injured neurons , 2006, Progress in Neurobiology.

[2]  E. Rugarli,et al.  Variable and Tissue-Specific Subunit Composition of Mitochondrial m-AAA Protease Complexes Linked to Hereditary Spastic Paraplegia , 2006, Molecular and Cellular Biology.

[3]  E. Rugarli,et al.  The m-AAA Protease Defective in Hereditary Spastic Paraplegia Controls Ribosome Assembly in Mitochondria , 2005, Cell.

[4]  Carmen Birchmeier,et al.  Axonal Neuregulin-1 Regulates Myelin Sheath Thickness , 2004, Science.

[5]  E. Rugarli,et al.  Axonal degeneration in paraplegin-deficient mice is associated with abnormal mitochondria and impairment of axonal transport. , 2004, The Journal of clinical investigation.

[6]  A. Ballabio,et al.  Loss of m-AAA protease in mitochondria causes complex I deficiency and increased sensitivity to oxidative stress in hereditary spastic paraplegia , 2003, The Journal of cell biology.

[7]  M. Filbin,et al.  Epitope-Tagged P0Glycoprotein Causes Charcot-Marie-Tooth–Like Neuropathy in Transgenic Mice , 2000, The Journal of cell biology.

[8]  P. Ronner,et al.  Luminometric assays of ATP, phosphocreatine, and creatine for estimation of free ADP and free AMP. , 1999, Analytical biochemistry.

[9]  W. Neupert,et al.  Chaperone-like activity of the AAA domain of the yeast Yme1 AAA protease , 1999, Nature.

[10]  Sergio Cocozza,et al.  Spastic Paraplegia and OXPHOS Impairment Caused by Mutations in Paraplegin, a Nuclear-Encoded Mitochondrial Metalloprotease , 1998, Cell.

[11]  H. Schägger,et al.  Analysis of molecular masses and oligomeric states of protein complexes by blue native electrophoresis and isolation of membrane protein complexes by two-dimensional native electrophoresis. , 1994, Analytical biochemistry.

[12]  Scott T. Brady,et al.  Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells , 1992, Cell.

[13]  B. Taylor,et al.  A mouse linkage testing stock possessing multiple copies of the endogenous ecotropic murine leukemia virus genome. , 1989, Genomics.

[14]  A J Harris,et al.  Nerve and muscle development in paralysé mutant mice. , 1989, Developmental biology.

[15]  Marinos C. Dalakas,et al.  Muscle biopsy — a practical approach , 1986, The Ulster Medical Journal.

[16]  R. Friede,et al.  Relation between the number of myelin lamellae and axon circumference in fibers of vagus and sciatic nerves of mice , 1967, The Journal of comparative neurology.

[17]  J. McKENDRICK,et al.  The Central Nervous System of Vertebrates , 1909, Nature.

[18]  B. Trapp,et al.  Cell Biology of Myelin Assembly , 2004 .

[19]  W. Frankel,et al.  A new strain congenic for the Mtv-7/Mls-1 locus of mouse chromosome 1 , 2004, Immunogenetics.

[20]  E. Rugarli,et al.  Protein quality control in mitochondria and neurodegeneration in hereditary spastic paraplegia , 2004 .

[21]  B. Robinson.  Use of fibroblast and lymphoblast cultures for detection of respiratory chain defects. , 1996, Methods in enzymology.