title: Loss of Miro1-directed mitochondrial movement results in a novel murine model for neuron disease.
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.
authors.affiliation: Departments of Biochemistry.
authors.forename: Tammy T
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Sang S
authors.initials: SS
authors.lastname: Oh
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: David
authors.initials: D
authors.lastname: Weaver
authors.affiliation: Departments of Biochemistry.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Lewandowska
authors.affiliation: Departments of Biology and.
authors.forename: Dane
authors.initials: D
authors.lastname: Maxfield
authors.affiliation: Departments of Biochemistry.
authors.forename: Max-Hinderk
authors.initials: MH
authors.lastname: Schuler
authors.affiliation: Departments of Biochemistry.
authors.forename: Nathan K
authors.initials: NK
authors.lastname: Smith
authors.affiliation: Departments of Biochemistry.
authors.forename: Jane
authors.initials: J
authors.lastname: Macfarlane
authors.affiliation: Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112; and.
authors.forename: Gerald
authors.initials: G
authors.lastname: Saunders
authors.affiliation: Pathology.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Palmer
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: Valentina
authors.initials: V
authors.lastname: Debattisti
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Koshiba
authors.affiliation: Neurology, University of Utah School of Medicine, Salt Lake City, UT 84112;
authors.forename: Stefan
authors.initials: S
authors.lastname: Pulst
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI 48109;
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
authors.affiliation: MitoCare Center, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107;
authors.forename: György
authors.initials: G
authors.lastname: Hajnóczky
authors.affiliation: Departments of Biochemistry, shaw@biochem.utah.edu.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Shaw
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001370:Axonal Transport / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology*; D009046:Motor Neurons / Q000378:metabolism; D010264:Paraplegia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D020741:rho GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C573782:Miro-1 protein, mouse; D000255:Adenosine Triphosphate; D020741:rho GTP-Binding Proteins; D002118:Calcium
keywords: Ca2+-dependent motility; Miro GTPase; mitochondrial respiration