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Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 21, 2018 (received for review June 27, 2018)
Significance
Neuritic retraction in the absence of overt neuronal death occurs during aging and early in neurodegenerative disorders. However, mechanisms responsible for physiologic and pathologic neuritic retraction are unknown. We demonstrate that progressive distal mitochondrial protein damage, resulting in impaired mitochondrial protein import in distal neuronal compartments, leads to the neurite loss-related focal caspase-3 activation. This import defect amplifies mitochondrial vulnerability by slowing incorporation of newly produced proteins, affecting mitochondrial physiology indicated by loss of membrane potential, increased reactive oxygen species production, and focal caspase-3 activation. We describe this fundamental physiologic mechanism that controls neurite plasticity/vulnerability and is further amplified during neurodegeneration as “neuritosis.” This neuronal regulatory mechanism is likely important for neurodevelopment and is exacerbated during aging and pathologically in neurodegenerative diseases.
Abstract
Neuritic retraction in the absence of overt neuronal death is a shared feature of normal aging and neurodegenerative disorders, but the intracellular mechanisms modulating this process are not understood. We propose that cumulative distal mitochondrial protein damage results in impaired protein import, leading to mitochondrial dysfunction and focal activation of the canonical apoptosis pathway in neurites. This is a controlled process that may not lead to neuronal death and, thus, we term this phenomenon “neuritosis.” Consistent with our hypothesis, we show that in primary cerebrocortical neurons, mitochondrial distance from the soma correlates with increased mitochondrial protein damage, PINK1 accumulation, reactive oxygen species production, and decreased mitochondrial membrane potential and depolarization threshold. Furthermore, we demonstrate that the distance-dependent mitochondrial membrane potential gradient exists in vivo in mice. We demonstrate that impaired distal mitochondria have a lower threshold for focal/nonlethal neuritic caspase-3 activation in normal neurons that is exacerbated in aging, stress, and neurodegenerative conditions, thus delineating a fundamental mechanistic underpinning for synaptic vulnerability.
Footnotes
- ↵1To whom correspondence should be addressed. Email: friedlanderr{at}upmc.edu.
Author contributions: S.V.B., O.V.B., and R.M.F. designed research; S.V.B., O.V.B., S.Y., Y.S., A.L.V., T.D.Y.K., X.T.C., L.M.F., T.M.L., and Y.Y.T. performed research; S.V.B., Y.Y.T., and V.E.K. analyzed data; and S.V.B., V.E.K., D.L.C., B.S.K., and R.M.F. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1811021116/-/DCSupplemental.
Published under the PNAS license.
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Mitochondria modulate programmed neuritic retraction
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