. Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. Proc Natl Acad Sci U S A. 2014 Aug 18; PubMed.

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  1. It is generally believed that the proper intracellular distribution of mitochondria, adapting to localized bioenergetic requirement, is critical for cellular physiology (Frazier et al., 2006). Despite previous studies nicely showing the regulation of mitochondrial mobility/distribution by Miro-1 in in vitro cultured cells (Saotome et al., 2008; Macaskill et al., 2009; Wang et al., 2009), the functional role of Miro-1 in vivo remains elusive.

    This elegant study, for the first time, provides clear and convincing evidence that Miro-1 was specifically required for upper motor neuron development and survival in mice in vivo. A critical question relevant to this study is why upper motor neurons are vulnerable to Miro-1 ablation. It would be interesting to know if the loss of Miro-1 in other types of cells, such as cortical neurons and muscle, is also sufficient to impair mitochondrial distribution/movement and cause cellular dysfunction in vivo.

    Mitochondrial movement deficits and altered mitochondrial distribution have been repeatedly reported in experimental models of motor neuron disease such as amyotrophic lateral sclerosis (ALS) (Magrane et al., 2014; Wang et al., 2013; Bilsland et al., 2010; De Vos et al., 2007). In this study, the authors showed that the neuronal specific loss of Miro-1 caused symptoms of motor neuron diseases, strongly supporting the possibility that mitochondrial distribution/movement deficits might be the cause rather than the consequence of motor neuron diseases. Miro-1 is a mitochondrial protein specifically regulating mitochondrial movement, and the in vivo system used in this study is relatively clean, especially considering the authors provided multiple lines of evidence demonstrating unchanged mitochondrial functions by Miro-1 ablation.

    Growing evidence suggests a critical role of mitochondria in the pathogenesis of neurodegenerative diseases including ALS, Alzheimer’s disease, and Parkinson’s disease. Although it still remains unclear whether Miro-1 or the machinery regulating mitochondrial movement/distribution is indeed altered in patients and experimental models of  neurodegenerative diseases, the Miro-1 floxed animal model used in this study is very useful and could be used to test whether and how the altered mitochondrial distribution contribute to disease onset and progression.

    References:

    . Mitochondrial morphology and distribution in mammalian cells. Biol Chem. 2006 Dec;387(12):1551-8. PubMed.

    . Bidirectional Ca2+-dependent control of mitochondrial dynamics by the Miro GTPase. Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20728-33. Epub 2008 Dec 19 PubMed.

    . Miro1 is a calcium sensor for glutamate receptor-dependent localization of mitochondria at synapses. Neuron. 2009 Feb 26;61(4):541-55. PubMed.

    . The mechanism of Ca2+ -dependent regulation of kinesin-mediated mitochondrial motility. Cell. 2009 Jan 9;136(1):163-74. PubMed.

    . Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum Mol Genet. 2014 Mar 15;23(6):1413-24. Epub 2013 Oct 23 PubMed.

    . The ALS disease-associated mutant TDP-43 impairs mitochondrial dynamics and function in motor neurons. Hum Mol Genet. 2013 Dec 1;22(23):4706-19. Epub 2013 Jul 4 PubMed.

    . Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci U S A. 2010 Nov 23;107(47):20523-8. Epub 2010 Nov 8 PubMed.

    . Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum Mol Genet. 2007 Nov 15;16(22):2720-8. Epub 2007 Aug 28 PubMed.

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  1. Mislocalized Mitochondria Sufficient for Motor Neuron Malaise