Loss of the m-AAA protease subunit AFG₃L₂ causes mitochondrial transport defects and tau hyperphosphorylation

EMBO J. 2014 May 2;33(9):1011-26. doi: 10.1002/embj.201387009. Epub 2014 Mar 28.


The m-AAA protease subunit AFG₃L₂ is involved in degradation and processing of substrates in the inner mitochondrial membrane. Mutations in AFG₃L₂ are associated with spinocerebellar ataxia SCA28 in humans and impair axonal development and neuronal survival in mice. The loss of AFG₃L₂ causes fragmentation of the mitochondrial network. However, the pathogenic mechanism of neurodegeneration in the absence of AFG₃L₂ is still unclear. Here, we show that depletion of AFG₃L₂ leads to a specific defect of anterograde transport of mitochondria in murine cortical neurons. We observe similar transport deficiencies upon loss of AFG₃L₂ in OMA1-deficient neurons, indicating that they are not caused by OMA1-mediated degradation of the dynamin-like GTPase OPA1 and inhibition of mitochondrial fusion. Treatment of neurons with antioxidants, such as N-acetylcysteine or vitamin E, or decreasing tau levels in axons restored mitochondrial transport in AFG₃L₂-depleted neurons. Consistently, tau hyperphosphorylation and activation of ERK kinases are detected in mouse neurons postnatally deleted for Afg3l2. We propose that reactive oxygen species signaling leads to cytoskeletal modifications that impair mitochondrial transport in neurons lacking AFG₃L₂.

MeSH terms

  • ATP-Dependent Proteases / genetics*
  • ATPases Associated with Diverse Cellular Activities
  • Acetylcysteine / pharmacology
  • Animals
  • Biological Transport / drug effects
  • Biological Transport / genetics
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Embryo, Mammalian
  • MAP Kinase Signaling System / genetics
  • Metalloproteases / genetics
  • Metalloproteases / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Mitochondrial Diseases / genetics
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation / genetics
  • Reactive Oxygen Species / pharmacology
  • tau Proteins / metabolism*


  • Mitochondrial Proteins
  • Reactive Oxygen Species
  • tau Proteins
  • Cyclic AMP-Dependent Protein Kinases
  • Metalloproteases
  • OMA1 protein, mouse
  • ATP-Dependent Proteases
  • Afg3l2 protein, mouse
  • ATPases Associated with Diverse Cellular Activities
  • Acetylcysteine