Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease

Tammy T. Nguyen, Sang S. Oh, David Weaver, Agnieszka Lewandowska, Dane Maxfield, Max Hinderk Schuler, Nathan K. Smith, Jane Macfarlane, Gerald Saunders, Cheryl A. Palmer, Valentina Debattisti, Takumi Koshiba, Stefan Pulst, Eva L. Feldman, György Hajnóczky, Janet M. Shaw

Research output: Contribution to journalArticle

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Abstract

Defective mitochondrial distribution in neurons is proposed to cause ATP depletion and calcium-buffering deficiencies that compromise cell function. However, it is unclear whether aberrant mitochondrial motility and distribution alone are sufficient to cause neurological disease. Calcium-binding mitochondrial Rho (Miro) GTPases attach mitochondria to motor proteins for anterograde and retrograde transport in neurons. Using two new KO mouse models, we demonstrate that Miro1 is essential for development of cranial motor nuclei required for respiratory control and maintenance of upper motor neurons required for ambulation. Neuron-specific loss of Miro1 causes depletion of mitochondria from corticospinal tract axons and progressive neurological deficits mirroring human upper motor neuron disease. Although Miro1-deficient neurons exhibit defects in retrograde axonal mitochondrial transport, mitochondrial respiratory function continues. Moreover, Miro1 is not essential for calcium-mediated inhibition of mitochondrial movement or mitochondrial calcium buffering. Our findings indicate that defects in mitochondrial motility and distribution are sufficient to cause neurological disease.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number35
DOIs
Publication statusPublished - Sep 2 2014

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Calcium
Neurons
Mitochondria
rho GTP-Binding Proteins
Motor Neuron Disease
Pyramidal Tracts
Axonal Transport
Motor Neurons
Walking
Axons
Adenosine Triphosphate
Maintenance
Proteins

All Science Journal Classification (ASJC) codes

  • General

Cite this

Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. / Nguyen, Tammy T.; Oh, Sang S.; Weaver, David; Lewandowska, Agnieszka; Maxfield, Dane; Schuler, Max Hinderk; Smith, Nathan K.; Macfarlane, Jane; Saunders, Gerald; Palmer, Cheryl A.; Debattisti, Valentina; Koshiba, Takumi; Pulst, Stefan; Feldman, Eva L.; Hajnóczky, György; Shaw, Janet M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 35, 02.09.2014.

Research output: Contribution to journalArticle

Nguyen, TT, Oh, SS, Weaver, D, Lewandowska, A, Maxfield, D, Schuler, MH, Smith, NK, Macfarlane, J, Saunders, G, Palmer, CA, Debattisti, V, Koshiba, T, Pulst, S, Feldman, EL, Hajnóczky, G & Shaw, JM 2014, 'Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 35. https://doi.org/10.1073/pnas.1402449111
Nguyen, Tammy T. ; Oh, Sang S. ; Weaver, David ; Lewandowska, Agnieszka ; Maxfield, Dane ; Schuler, Max Hinderk ; Smith, Nathan K. ; Macfarlane, Jane ; Saunders, Gerald ; Palmer, Cheryl A. ; Debattisti, Valentina ; Koshiba, Takumi ; Pulst, Stefan ; Feldman, Eva L. ; Hajnóczky, György ; Shaw, Janet M. / Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 35.
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