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Loss of the m‐ AAA protease subunit AFG 3L2 causes mitochondrial transport defects and tau hyperphosphorylation
Author(s) -
Kondadi Arun Kumar,
Wang Shuaiyu,
Montagner Sara,
Kladt Nikolay,
Korwitz Anne,
Martinelli Paola,
Herholz David,
Baker Michael J,
Schauss Astrid C,
Langer Thomas,
Rugarli Elena I
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1002/embj.201387009
Subject(s) - biology , protein subunit , hyperphosphorylation , protease , mitochondrion , microbiology and biotechnology , transport protein , biochemistry , enzyme , phosphorylation , gene
The m ‐ AAA protease subunit AFG 3L2 is involved in degradation and processing of substrates in the inner mitochondrial membrane. Mutations in AFG 3L2 are associated with spinocerebellar ataxia SCA 28 in humans and impair axonal development and neuronal survival in mice. The loss of AFG 3L2 causes fragmentation of the mitochondrial network. However, the pathogenic mechanism of neurodegeneration in the absence of AFG 3L2 is still unclear. Here, we show that depletion of AFG 3L2 leads to a specific defect of anterograde transport of mitochondria in murine cortical neurons. We observe similar transport deficiencies upon loss of AFG 3L2 in OMA 1 ‐deficient neurons, indicating that they are not caused by OMA 1‐mediated degradation of the dynamin‐like GTP ase OPA 1 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 3L2‐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 3L2.