| First Author | Kondadi AK | Year | 2014 |
| Journal | EMBO J | Volume | 33 |
| Issue | 9 | Pages | 1011-26 |
| PubMed ID | 24681487 | Mgi Jnum | J:210967 |
| Mgi Id | MGI:5572979 | Doi | 10.1002/embj.201387009 |
| Citation | Kondadi AK, et al. (2014) Loss of the m-AAA protease subunit AFG(3)L(2) causes mitochondrial transport defects and tau hyperphosphorylation. EMBO J 33(9):1011-26 |
| abstractText | The m-AAA protease subunit AFG(3)L(2) is involved in degradation and processing of substrates in the inner mitochondrial membrane. Mutations in AFG(3)L(2) are associated with spinocerebellar ataxia SCA28 in humans and impair axonal development and neuronal survival in mice. The loss of AFG(3)L(2) causes fragmentation of the mitochondrial network. However, the pathogenic mechanism of neurodegeneration in the absence of AFG(3)L(2) is still unclear. Here, we show that depletion of AFG(3)L(2) leads to a specific defect of anterograde transport of mitochondria in murine cortical neurons. We observe similar transport deficiencies upon loss of AFG(3)L(2) 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 AFG(3)L(2)-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 AFG(3)L(2). |
