Abstract
Mitochondrial dynamics is a key process that modulates the ultrastructure, quality and function of mitochondria. It is disrupted in numerous major neurodegenerative disorders including Parkinson’s, Alzheimer’s and Huntington’s disease. Mitochondrial dysfunction has been correlated with the loss of memory. Previous studies suggest the involvement of Vdac1 and Drp1 in outer mitochondrial membrane permeabilization and promotion of mitochondrial fragmentation through Drp1 phosphorylation at S616. However, alterations in mitochondrial dynamics with respect to aging, memory loss and neurodegeneration remain unexplored. Therefore, the present study focuses on the involvement of mitochondrial dynamics in neurodegeneration and recognition memory decline during aging. The recognition memory decline was validated by the novel object recognition test and measurement of hippocampal Arc protein level during aging. The ultrastructure analysis revealed a decline in mitochondrial length and area, while an increase in the number of fragmented, round and disrupted mitochondria in the hippocampus during aging. Disruption was also evident in mitochondrial cristae and membrane with advancing age. The change in mitochondrial morphology was corroborated by an increase in the expression of phospho-Drp1 (S616) and Cyt-c proteins but decline in Mfn2, LC3B, Vdac1, Bcl-XL and Bcl-2 proteins in the hippocampus during aging. Taken together, our findings reveal that an increase in the expression of phospho-Drp1 (S616) and decrease in Mfn2 and LC3B proteins in the hippocampus bring about a reduction in mitochondrial length and area, and rise in mitochondrial fragmentation leading to reduced neuronal cell density, increased neurodegeneration and recognition memory decline in old male mice.
Graphical abstract
Diagram depicts the increase in hippocampal mitochondrial fragmentation during aging of mice. Increased mitochondrial fragmentation causes distorted mitochondrial function such as decrease in ATP/ADP transportation due to decrease in Vdac1 protein level and increase in oxidative damage. These alterations result in hippocampal neurodegeneration and consequently impairment in recognition memory during aging.
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Abbreviations
- AD:
-
Alzheimer’s disease
- ATP:
-
Adenosine triphosphate
- Drp-1:
-
Dynamin-related protein-1
- H:
-
Hour
- H2O2 :
-
Hydrogen peroxide
- µg:
-
Micro gram
- µm:
-
Micro meter
- M:
-
Mitochondria
- Mfn:
-
Mitofusin
- mM:
-
Millimolar
- mg:
-
Milligram
- Min:
-
Minute
- MMP:
-
Mitochondrial membrane potential
- NOR:
-
Novel object recognition
- RDV:
-
Relative density value
- ROS:
-
Reactive oxygen species
- SEM:
-
Standard error of mean
- TEM:
-
Transmission electron microscopy
- qRT-PCR:
-
Quantitative Real-time PCR
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Acknowledgements
The authors acknowledge the qRT-PCR and fluorescent microscopy facilities of Interdisciplinary School of Life Sciences, BHU. Ela Mishra thanks the Council of Scientific and Industrial Research, India for Junior and Senior Research Fellowships.
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The work was supported by grants from the University Grants Commission (F.18-1/2011, BSR), Indian Council of Medical Research (5/4-5/153/Neuro/2015-NCD-I) and Department of Science & Technology (EMR/2015/002178), Government of India to MKT.
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EM conceptualized work, performed experiments, analysed data, wrote original draft with input from MKT; MKT conceptualized work, supervised, funding acquisition, reviewed and edited the manuscript.
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Mishra, E., Thakur, M.K. Alterations in hippocampal mitochondrial dynamics are associated with neurodegeneration and recognition memory decline in old male mice. Biogerontology 23, 251–271 (2022). https://doi.org/10.1007/s10522-022-09960-3
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DOI: https://doi.org/10.1007/s10522-022-09960-3