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

Authors

Tammy T Nguyen, Department of Biochemistry, University of Utah School of Medicine
Sang S Oh, Department of Neurology, University of Michigan, Ann Arbor,
David Weaver, MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson UniversityFollow
Agnieszka Lewandowska, Department of Biochemistry, University of Utah School of Medicine
Dane Maxfield, Department of Biology, University of Utah, Salt Lake City
Max-Hinderk Schuler, Department of Biochemistry, University of Utah School of Medicine
Nathan K Smith, Department of Biochemistry, University of Utah School of Medicine
Jane Macfarlane, Department of Biochemistry, University of Utah School of Medicine
Gerald Saunders, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City
Cheryl A Palmer, Department of Pathology, University of Utah School of Medicine, Salt Lake City
Valentina Debattisti, MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson UniversityFollow
Takumi Koshiba, Department of Biology, Faculty of Sciences, Kyushu University
Stefan Pulst, Department of Neurology, University of Utah School of Medicine, Salt Lake City
Eva L Feldman, Department of Neurology, University of Michigan, Ann Arbor,
György Hajnóczky, MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson UniversityFollow
Janet M Shaw, Department of Biochemistry, University of Utah School of Medicine

Document Type

Article

Publication Date

9-2-2014

Comments

This article has been peer reviewed. It was published in: Proceedings of the National Academy of Sciences of the United States of America.

Volume 111, Issue 35, 2 September 2014, Pages E3631-E3640.

The published version is available at DOI: 10.1073/pnas.1402449111

Copyright © the authors

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.

Recommended Citation

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; and Shaw, Janet M, "Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease." (2014). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 150.
https://jdc.jefferson.edu/pacbfp/150

PubMed ID

25136135