The E3 Ubiquitin Ligase MARCH5: Integral Membrane Domain Links Mitochondria to Neurodegeneration in Alzheimer's Disease

摘要

Mitochondrial dynamics is the process during which mitochondria undergo fission or fusion in order to regulate their health and number. When mitochondria do not function properly this affects many processes such as the generation of ATP and Ca~(2+) regulation [1] and proper localization of mitochondria, especially in neurons [2]. The number of neurodegenerative diseases, including Alzheimer's Disease (AD), that have been linked to changes in mitochondrial dynamics have been increasing [1,3-8]. The proteins that are known to be involved in both fusion and fission of the mitochondria are nuclear encoded and then targeted to the organelle. The proteins involved in both fusion [9-11] (Mfnl, Mfn2 and OPA1) and fission [12,13] (Drpl and hFisl) appear to be regulated by the mitochondrial membrane-bound E3 ubiquitin ligase, MARCH5. It was found to interact with and ubiquitinate both Mfnl and Mfn2 [14-16] and both Drpl and hFisl have been shown to coimmunoprecipitate with it [16]. Furthermore, the functions of MARCH5 and Drpl appear to be codependent as stable fission complexes are dependent on the presence of both proteins [16]. Mutations of the domain responsible for the ubiquitination activity cause changes in the appearance of the mitochondria in mammalian cell lines [16,17]. The ubiquitination helps to maintain a functional balance of the mitochondrial dynamics that results in proper regulation of the mitochondria [14-16,18]. The reliance of both fission and fusion on proper function of MARCH5 indicates that it may be a central processing point for proteins involved in mitochondrial dynamics.