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High cyclophilin D content of synaptic mitochondria results in increased vulnerability to permeability transition

Kranthi Kumari Naga1, Patrick G Sullivan, James W Geddes

  • 1Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, Kentucky 40536, USA.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|July 13, 2007
PubMed

Insights

Synaptic mitochondria are more vulnerable to calcium overload due to higher cyclophilin D levels, primarily from neuronal mitochondria. This explains their increased sensitivity to mitochondrial permeability transition pore opening.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Mitochondrial Biology

Background:

  • Synaptic mitochondria exhibit greater sensitivity to calcium (Ca2+) overload and mitochondrial permeability transition pore (mPTP) opening compared to nonsynaptic mitochondria.
  • Understanding the molecular basis for these Ca2+ handling differences is crucial for comprehending neuronal function and dysfunction.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the differential Ca2+ handling between synaptic and nonsynaptic mitochondria.
  • To determine the role of cyclophilin D in mediating these Ca2+ dynamics.

Main Methods:

  • Comparative analysis of mPTP component levels (cyclophilin D, VDAC, ANT) in isolated synaptic and nonsynaptic mitochondria.
  • Assessment of Ca2+ handling and mPTP opening in wild-type and cyclophilin D null (Ppif-/-) mice.
  • Evaluation of cyclophilin D expression in primary cortical neurons and astrocytes.
  • Immunohistochemical analysis of cyclophilin D distribution in the adult rat brain.

Main Results:

  • Synaptic mitochondria possess significantly higher levels of cyclophilin D compared to nonsynaptic mitochondria; VDAC and ANT levels were similar.
  • Ca2+ handling differences were diminished in Ppif-/- mice, indicating cyclophilin D's critical role.
  • Higher cyclosporine A concentrations were required to inhibit mPTP opening in synaptic mitochondria.
  • Primary neurons exhibited higher cyclophilin D levels than astrocytes, with abundant neuronal cyclophilin D immunoreactivity in the brain.

Conclusions:

  • The heightened Ca2+ sensitivity and mPTP opening in synaptic mitochondria are primarily attributed to elevated cyclophilin D levels, largely due to the higher proportion of neuronal mitochondria.
  • Neuronal mitochondria's high cyclophilin D content renders them more susceptible to mPTP-mediated events, necessitating higher cyclosporine A concentrations for inhibition.

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