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Normal mitochondrial respiratory function is essential for spatial remote memory in mice
Daisuke Tanaka1, Kazuto Nakada, Keizo Takao
1University of Tsukuba, Ibaraki, Japan. s0630475@ipe.tsukuba.ac.jp
Background:
Mitochondrial DNA (mtDNA) with pathogenic mutations has been found in patients with cognitive disorders. However, little is known about whether pathogenic mtDNA mutations and the resultant mitochondrial respiration deficiencies contribute to the expression of cognitive alterations, such as impairments of learning and memory. To address this point, we used two groups of trans-mitochondrial mice (mito-mice) with heteroplasmy for wild-type and pathogenically deleted (Δ) mtDNA; the "low" group carried 50% or less ΔmtDNA, and the "high" group carried more than 50% ΔmtDNA.
Results:
Both groups had normal phenotypes for not only spatial learning, but also memory at short retention delays, indicating that ΔmtDNA load did not affect learning and temporal memory. The high group, however, showed severe impairment of memory at long retention delays. In the visual cortex and dentate gyrus of these mice, we observed mitochondrial respiration deficiencies, and reduced Ca²(+)/calmodulin-dependent kinase II-α (α-CaMKII), a protein important for the establishment of spatial remote memory.
Conclusion:
Our results indicated that normal mitochondrial respiratory function is necessary for retention and consolidation of memory trace; deficiencies in this function due to high loads of pathogenically mutated mtDNA are responsible for the preferential impairment of spatial remote memory.
Insights
Pathogenic mitochondrial DNA (mtDNA) mutations impair spatial remote memory. High loads of mutated mtDNA cause deficiencies in mitochondrial respiration, leading to memory deficits.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Pathogenic mitochondrial DNA (mtDNA) mutations are linked to cognitive disorders.
- The role of mtDNA mutations and mitochondrial dysfunction in cognitive alterations like memory impairment remains unclear.
Purpose of the Study:
- To investigate the impact of pathogenic mtDNA mutations and mitochondrial respiration deficiencies on learning and memory.
- To determine if increased loads of mutated mtDNA cause cognitive deficits.
Main Methods:
- Utilized two groups of trans-mitochondrial mice (mito-mice) with varying heteroplasmy levels for wild-type and deleted (Δ) mtDNA.
- Assessed spatial learning and memory retention at short and long delays.
- Examined mitochondrial respiration and key protein expression in brain regions.
Main Results:
- Mice with low ΔmtDNA loads showed normal spatial learning and short-term memory.
- Mice with high ΔmtDNA loads exhibited severe impairment in long-term spatial memory retention.
- Mitochondrial respiration deficiencies and reduced α-CaMKII were observed in the high ΔmtDNA group.
Conclusions:
- Normal mitochondrial respiratory function is crucial for memory consolidation and retention.
- High levels of pathogenic mtDNA mutations lead to mitochondrial dysfunction, preferentially impairing spatial remote memory.
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