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    Mitochondrial dysfunction plays a critical role in the pathophysiology of Parkinson's disease (PD). The inner mitochondrial membrane (IMM) protein, Mitofilin or Mic60, has been shown to play a key role in controlling and maintaining mitochondrial cristae morphology, and its dysregulation induces cyto-deleterious effects. Here, we investigated the mechanism underlying Mitofilin degradation in dopaminergic neuron death using N27-A cells, and Human Dopamine Neuronal Primary cells treated with PD stressors, Dopamine (DA) or Rotenone (Rot). We found that both PD stressors increased mitochondrial Parkin translocation and interaction with Mitofilin that promotes Mitofilin degradation via ubiquitination, which is responsible for reduced mitochondrial membrane potential and increased ROS production. These effects were concomitant with abnormal mitochondrial structure and increased neuronal death. DA-induced degradation of Mitofilin enhances mitochondrial calpain activity, increases the release of AIF into the cytosol, and promotes apoptosis via an AIF-PARP dependent mechanism. We found that Rot-treated cells exhibit excessive mitophagy, while DA does not trigger mitophagy. In addition, overexpressing USP30, a mitochondrial deubiquitinase, attenuated cell death induced by Rot, but not by DA-treated cells. Together, our study reveals the impact of Parkin-Mitofilin interaction in PD stressor-induced neurotoxicity, which leads to the degradation of Mitofilin, resulting in mitochondrial structural damage and dysfunction that is responsible for neuronal death by apoptosis via an AIF-PARP pathway. AJTR Copyright © 2020.

    Citation

    Abdulhafiz D Imam Aliagan, Mina D Ahwazi, Nathalie Tombo, Yansheng Feng, Jean C Bopassa. Parkin interacts with Mitofilin to increase dopaminergic neuron death in response to Parkinson's disease-related stressors. American journal of translational research. 2020;12(11):7542-7564


    PMID: 33312388

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