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Edited by Thomas L. Schwarz, Children's Hospital, Boston, MA, and accepted by the Editorial Board July 13, 2015 (received for review May 27, 2015)
Significance
The lack of intravital imaging of axonal transport of mitochondria in the living mammalian CNS precludes the characterization of transport dynamics in the diseased and aged mammalian CNS. Here we report minimally invasive intravital multiphoton imaging of mouse retinal ganglion cells that offers sequential time-lapse images of mitochondria transported in a single axon with submicrometer resolution. We show highly dynamic axonal transport of mitochondria in the mammalian CNS in vivo under physiological conditions and characterize disturbances of mitochondrial transport in a mouse glaucoma model and age-related changes in mitochondrial transport. Our method is useful for characterizing the dynamics of axonal transport of mitochondria and the dynamics of other submicrometer structures in the diseased and aged mammalian CNS in vivo.
Abstract
The lack of intravital imaging of axonal transport of mitochondria in the mammalian CNS precludes characterization of the dynamics of axonal transport of mitochondria in the diseased and aged mammalian CNS. Glaucoma, the most common neurodegenerative eye disease, is characterized by axon degeneration and the death of retinal ganglion cells (RGCs) and by an age-related increase in incidence. RGC death is hypothesized to result from disturbances in axonal transport and in mitochondrial function. Here we report minimally invasive intravital multiphoton imaging of anesthetized mouse RGCs through the sclera that provides sequential time-lapse images of mitochondria transported in a single axon with submicrometer resolution. Unlike findings from explants, we show that the axonal transport of mitochondria is highly dynamic in the mammalian CNS in vivo under physiological conditions. Furthermore, in the early stage of glaucoma modeled in adult (4-mo-old) mice, the number of transported mitochondria decreases before RGC death, although transport does not shorten. However, with increasing age up to 23–25 mo, mitochondrial transport (duration, distance, and duty cycle) shortens. In axons, mitochondria-free regions increase and lengths of transported mitochondria decrease with aging, although totally organized transport patterns are preserved in old (23- to 25-mo-old) mice. Moreover, axonal transport of mitochondria is more vulnerable to glaucomatous insults in old mice than in adult mice. These mitochondrial changes with aging may underlie the age-related increase in glaucoma incidence. Our method is useful for characterizing the dynamics of axonal transport of mitochondria and may be applied to other submicrometer structures in the diseased and aged mammalian CNS in vivo.
Footnotes
- ↵ 1To whom correspondence should be addressed. Email: inatani{at}u-fukui.ac.jp.
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Author contributions: Y. Takihara, M.I., and J.L.G. designed research; Y. Takihara, M.I., K.E., T.I., A.K., S.M., S.U., M.N., A.N., K.I., Y. Takamura, H.S., K.S., M.K., T.S., J.N., and H.T. performed research; Y. Takihara, M.I., K.E., and J.N. contributed new reagents/analytic tools; Y. Takihara, M.I., K.E., T.I., A.K., S.M., S.U., M.N., A.N., K.I., Y. Takamura, H.S., K.S., M.K., T.S., J.L.G., J.N., and H.T. analyzed data; and Y. Takihara and M.I. wrote the paper.
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The authors declare no conflict of interest.
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This article is a PNAS Direct Submission. T.L.S. is a guest editor invited by the Editorial Board.
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This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1509879112/-/DCSupplemental.
Freely available online through the PNAS open access option.
Axonal transport of mitochondria in mammalian CNS
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