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Author Notes:

Corresponding authors: Pasko Rakic, M.D., Ph.D and Yury Morozov, Ph.D, Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, SHM, C‐303, New Haven, Connecticut, USA 06510, Tel.: (203) 785-4330, Fax: (203) 785-5263, Email: pasko.rakic@yale.edu Email: yury.morozov@yale.edu

Y.M.M. initiated the project, performed experiments and wrote the article.

Y.Y.S. performed tHI; C.-Y. K. and P.R. analyzed the data and wrote the article.

The authors declare no competing financial interests. We are grateful to Ruth Rappaport, Ph.D. for her editorial assistance in preparation of the manuscript.

Subjects:

Research Funding:

This research was supported by Kavli Institute for Neuroscience at Yale and the National Institute of Health grants DA023999, NS014841 and R01EY002593 (to P.R.) and NS084744 (to C.-Y.K.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • antibody cross-reactivity
  • biomarker
  • CB1
  • mitochondrial permeability transition
  • MPTP complex
  • SLP2
  • STOMATIN-LIKE PROTEIN-2
  • CANNABINOID-INDUCED CHANGES
  • MEMBRANE PERMEABILIZATION
  • RAT HIPPOCAMPUS
  • INNER MEMBRANE
  • INTERNEURONS
  • STRESS
  • TRANSLOCATION
  • RESPIRATION
  • CARDIOLIPIN

Alteration of SLP2-like immunolabeling in mitochondria signifies early cellular damage in developing and adult mouse brain

Tools:

Journal Title:

European Journal of Neuroscience

Volume:

Volume 43, Number 2

Publisher:

, Pages 245-257

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Mitochondria play a critical role in various pathways of regulated cell death. Here we propose a novel method for detection of initial derangement of mitochondria in degenerating and dying neuronal cells. The method is based on our recent finding that antibodies directed against the cannabinoid type 1 receptor (CB1) also bind the mitochondrial stomatin-like protein 2 (SLP2) that belongs to an inner mitochondrial membrane protein complex. It is well established that SLP2 regulates mitochondrial biogenesis and respiratory functions. We now show that anti-CB1 antibodies recognize conformational epitopes but not the linear amino acid sequence of SLP2. In addition we found that anti-CB1 serum mostly labels swollen mitochondria with early or advanced stages of pathology in mouse brain while other proteins of the complex may mask epitopes of SLP2 in the normal mitochondria. Although neurons and endothelial cells in healthy brains contain occasional immunopositive mitochondria detectable with anti-CB1 serum, their numbers increase significantly after hypoxic insults in parallel with signs of cellular damage. Moreover, use of electron microscopy suggests relocation of SLP2 from its normal functional position in the inner mitochondrial membrane into the mitochondrial matrix in pathological cells. Thus, SLP2-like immunolabeling serves as an in situ histochemical target detecting early derangement of mitochondria. Anti-CB1 serum is crucial for this purpose because available anti-SLP2 antibodies do not provide selective labeling of mitochondria in the fixed tissue. This new method of detecting mitochondrial dysfunction can benefit the in vitro research of human diseases and developmental disorders by enabling analysis in live animal models.

Copyright information:

© 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

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