Rapid Intramitochondrial Zn2+ Accumulation in CA1 Hippocampal Pyramidal Neurons After Transient Global Ischemia: A Possible Contributor to Mitochondrial Disruption and Cell Death

J Neuropathol Exp Neurol. 2019 Jul 1;78(7):655-664. doi: 10.1093/jnen/nlz042.

Abstract

Mitochondrial Zn2+ accumulation, particularly in CA1 neurons, occurs after ischemia and likely contributes to mitochondrial dysfunction and subsequent neurodegeneration. However, the relationship between mitochondrial Zn2+ accumulation and their disruption has not been examined at the ultrastructural level in vivo. We employed a cardiac arrest model of transient global ischemia (TGI), combined with Timm's sulfide silver labeling, which inserts electron dense metallic silver granules at sites of labile Zn2+ accumulation, and used transmission electron microscopy (TEM) to examine subcellular loci of the Zn2+ accumulation. In line with prior studies, TGI-induced damage to CA1 was far greater than to CA3 pyramidal neurons, and was substantially progressive in the hours after reperfusion (being significantly greater after 4- than 1-hour recovery). Intriguingly, TEM examination of Timm's-stained sections revealed substantial Zn2+ accumulation in many postischemic CA1 mitochondria, which was strongly correlated with their swelling and disruption. Furthermore, paralleling the evolution of neuronal injury, both the number of mitochondria containing Zn2+ and the degree of their disruption were far greater at 4- than 1-hour recovery. These data provide the first direct characterization of Zn2+ accumulation in CA1 mitochondria after in vivo TGI, and support the idea that targeting these events could yield therapeutic benefits.

Keywords: Excitotoxicity; Hippocampus; Ischemia; Mitochondria; Rat; Stroke; Zinc.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / cytology
  • CA1 Region, Hippocampal / metabolism*
  • CA1 Region, Hippocampal / pathology
  • CA3 Region, Hippocampal / cytology
  • CA3 Region, Hippocampal / metabolism
  • CA3 Region, Hippocampal / pathology
  • Cell Death
  • Ischemic Attack, Transient / metabolism*
  • Ischemic Attack, Transient / pathology
  • Male
  • Mitochondria / metabolism*
  • Mitochondria / pathology
  • Mitochondria / ultrastructure
  • Mitochondrial Swelling
  • Pyramidal Cells / metabolism*
  • Rats
  • Rats, Wistar
  • Zinc / metabolism*

Substances

  • Zinc