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.
Lack of the m-AAA protease subunit AFG3L2 impairs anterograde axonal transport of mitochondria via a mechanism that involves ROS signaling and hyperphosphorylation of the microtubule-associated protein tau.
- Depletion of AFG3L2 in cortical neurons leads to a specific defect of anterograde axonal transport of mitochondria.
- The mitochondrial transport defect is independent from OMA1-dependent OPA1 processing.
- Anterograde axonal transport of mitochondria in AFG3L2-depleted neurons is rescued by reducing tau levels and by treatment with antioxidants.
- Deletion of Afg3l2 in cortical neurons activates ERK kinases and leads to tau hyperphosphorylation.