期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 35, 页码 E3631-E3640出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1402449111
关键词
Ca2+-dependent motility; Miro GTPase; mitochondrial respiration
资金
- National Institutes of Health [GM84970, GM53466, F31 NS080342, R01 NS033123, DK051526, R24 082841]
- American Diabetes Association, Program for Neurology Research and Discovery
- A. Alfred Taubman Medical Research Institute
- Japan Society for the Promotion of Science [KAKENHI 25115515]
- National Multiple Sclerosis Society
- Grants-in-Aid for Scientific Research [25115515, 26291032, 26620135] Funding Source: KAKEN
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.
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