Variable and tissue-specific subunit composition of mitochondrial m-AAA protease complexes linked to hereditary spastic paraplegia

Mol Cell Biol. 2007 Jan;27(2):758-67. doi: 10.1128/MCB.01470-06. Epub 2006 Nov 13.


The m-AAA protease, an ATP-dependent proteolytic complex in the mitochondrial inner membrane, controls protein quality and regulates ribosome assembly, thus exerting essential housekeeping functions within mitochondria. Mutations in the m-AAA protease subunit paraplegin cause axonal degeneration in hereditary spastic paraplegia (HSP), but the basis for the unexpected tissue specificity is not understood. Paraplegin assembles with homologous Afg3l2 subunits into hetero-oligomeric complexes which can substitute for yeast m-AAA proteases, demonstrating functional conservation. The function of a third paralogue, Afg3l1 expressed in mouse, is unknown. Here, we analyze the assembly of paraplegin into m-AAA complexes and monitor consequences of paraplegin deficiency in HSP fibroblasts and in a mouse model for HSP. Our findings reveal variability in the assembly of m-AAA proteases in mitochondria in different tissues. Homo-oligomeric Afg3l1 and Afg3l2 complexes and hetero-oligomeric assemblies of both proteins with paraplegin can be formed. Yeast complementation studies demonstrate the proteolytic activity of these assemblies. Paraplegin deficiency in HSP does not result in the loss of m-AAA protease activity in brain mitochondria. Rather, homo-oligomeric Afg3l2 complexes accumulate, and these complexes can substitute for housekeeping functions of paraplegin-containing m-AAA complexes. We therefore propose that the formation of m-AAA proteases with altered substrate specificities leads to axonal degeneration in HSP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Dependent Proteases
  • ATPases Associated with Diverse Cellular Activities
  • Adenosine Triphosphatases / metabolism
  • Animals
  • Axons / metabolism
  • Brain / metabolism
  • Brain / ultrastructure
  • Humans
  • Hydrolysis
  • Metalloendopeptidases / genetics
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Spastic Paraplegia, Hereditary / genetics
  • Spastic Paraplegia, Hereditary / metabolism*


  • Mitochondrial Proteins
  • Protein Subunits
  • Saccharomyces cerevisiae Proteins
  • ATP-Dependent Proteases
  • AFG3L2 protein, human
  • Metalloendopeptidases
  • Spg7 protein, mouse
  • m-AAA proteases
  • Adenosine Triphosphatases
  • ATPases Associated with Diverse Cellular Activities