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.
Maltecca
Francesca
F
Human Molecular Genetics Unit, and Neuropathology Unit and Istituto di Neurologia Sperimentale, San Raffaele Scientific Institute, 20132 Milan, Italy.
Aghaie
Asadollah
A
Schroeder
David G
DG
Cassina
Laura
L
Taylor
Benjamin A
BA
Phillips
Sandra J
SJ
Malaguti
Mariachiara
M
Previtali
Stefano
S
Guénet
Jean-Louis
JL
Quattrini
Angelo
A
Cox
Gregory A
GA
Casari
Giorgio
G
D049069:ATP-Dependent Proteases; D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000096:biosynthesis* / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000201:enzymology* / Q000473:pathology / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data
D024101:Mitochondrial Proteins; D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities