Mitochondrial division is mediated by the conserved dynamin-related GTPase DNM1L/DRP1. DNM1L assembles onto the surface of mitochondria and constricts this tubular organelle. Alterations in mitochondrial division are linked to many neurodegenerative diseases. However, the in vivo function of mitochondrial division is poorly understood. In our recent paper, we studied the physiological role of mitochondrial division in postmitotic neurons using the cre-loxP system. We found that the loss of DNM1L resulted in increased oxidative damage in mitochondria, impaired respiration and neurodegeneration in postmitotic neurons. Suggesting a decrease in mitochondrial turnover, mitophagy-related proteins such as LC3, SQSTM1/p62 and ubiqutin accumulated in division-defective mitochondria. These findings suggest that mitochondrial division functions as an important quality control mechanism that suppresses oxidative damage and neurodegeneration in vivo class="kwd-title">Keywords: mitochondrial division, DNM1L/DRP1, neurodegeneration, oxidative stress, mitophagy, parkinMitochondria continuously divide and fuse, and the balance between division and fusion determines organelle size, number and morphology. In many cell types, such as mouse embryonic fibroblasts (MEFs), the loss of mitochondrial division leads to interconnected, elongated mitochondria due to unopposed fusion, and the loss of mitochondrial fusion generates many small mitochondria due to ongoing division. Mitochondrial division is mediated by the dynamin-related GTPase DNM1L, which drives constriction by assembling into filaments around mitochondria through interactions with DNM1L receptor proteins. Studies on human diseases have suggested that neurons are highly dependent on mitochondrial division for their survival. For example, a mutation in DNM1L causes postneonatal death accompanied by neurodegeneration. In addition, alterations in mitochondrial division have been implicated in many aging-related neurodegenerative disorders such as Alzheimer, Huntington and Parkinson diseases. Therefore, it is important to understand the role of mitochondrial division in neurons and other cell types. However, it is largely unknown why mitochondria divide. In our recent paper, we investigated the physiological and cellular function of DNM1L in postmitotic neurons using animal and cell culture systems, with particular focus on cerebellar Purkinje cells since these neurons highly express DNM1L.We deleted Dnm1l specifically in postmitotic Purkinje cells by crossing mice that carry a floxed allele of Dnm1l to a transgenic mouse line that expresses cre recombinase from the Purkinje cell-specific L7 promoter at 1 mo of age (L7-Drp1KO mice). Upon the loss of DNM1L, mitochondria, which are short tubules in the wild type, elongated and then became large spheres (). We found similar changes in mitochondrial morphology when Dnm1l was deleted in cultured Purkinje cells in vitro. This large, spherical morphology was in sharp contrast to the interconnected, long tubules of mitochondria observed in Dnm1l-null MEFs. The mitochondria in Dnm1l-null Purkinje cells accumulated oxidative damage as shown by immunofluorescence with anti-hydroxynonenal antibodies, which recognize peroxidation of proteins and lipids. This oxidative damage was responsible for the formation of large spherical mitochondria, since treating with antioxidants such as N-acetylcysteine, coenzyme Q10 and mito Q resulted in elongated mitochondria similar to those of Dnm1l-null MEFs. Supporting this notion, treating Dnm1l-null MEFs with hydrogen peroxide converted elongated mitochondrial tubules into large round structures.>Figure 1. Mitochondrial division is essential for the maintenance of mitochondrial function in Purkinje cells.
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