Normal mitochondrial respiratory function is essential for spatial remote memory in mice

Abstract

BackgroundMitochondrial 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.ResultsBoth 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.ConclusionOur 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.

Transmitochondrial Mice as Models for Mitochondrial DNA-Based Diseases

“…Thus, the use of mito-mice∆ could provide unambiguous evidence that pathological phenotypes exclusively observed in mito-mice∆ carrying high loads of ∆mtDNA are caused by ∆mtDNA-induced mitochondrial respiration defects. Our experiments clearly showed that loads of 50% or less ∆mtDNA did not induce mitochondrial respiration deficiencies in the brain tissues and were also not associated with behavioral abnormalities, whereas loads of more than 60% were able to induce mitochondrial respiration defects and downregulation of CaM kinase II subunit alpha in brain tissues, leading to impairment of spatial remote memory [41].…”

“…On the basis of our findings, we suggest that some cases of human memory defect are caused by high loads of pathogenic mutant mtDNA and the resultant mitochondrial respiration defects [41]. We also suggest that improving mitochondrial respiration and/or location of CaM kinase II subunit alpha might be effective strategies for treating memory disorders, although there are biological differences between such disorders in humans and mice.…”

“…Mito-mice with a high load of ∆mtDNA showed mitochondrial disease phenotypes due to mitochondrial respiration defects, such as low body weight, lactic acidosis, systemic ischemia, auriculoventricular block with Wenckebach periodicity, hearing loss, renal failures, and male infertility [16,17,[26][27][28][29]41]. Lactic acidosis is one of the typical clinical phenotypes in patients with mitochondrial respiration defects, and the symptom suggests acceleration of the glycolytic pathway for producing ATP without mitochondrial respiration.…”

“…3) [16,36]. In the case of mito-mice∆ carrying more than 70% ∆mtDNA at birth, the mitomice∆ showed mitochondrial respiration defects and disease phenotypes and consequently died at around 6 months after birth [16,17,[26][27][28][29]41]. On the other hand, mito-mice carrying about 30-50% ∆mtDNA at the birth were healthy, but they expressed mitochondrial respiration defects and disease phenotypes and died by around 1.5 years after birth when the∆mtDNA load became 75-85%.…”

Neuropathological characterization of FL-PGC-1α-deficient mice – implications for mitochondrial encephalopathy

“…Collectively, this pattern is highly reminiscent of human mitochondrial spongiform encephalopathies, particularly of KSS and, in some aspects, LS (Table 2) ERRγ [123], NRF-1 [124], NRF-2 [125], Tfam [126], mtDNA polymerase γ 1 (POLG1) [127], optic atrophy 1 (OPA1) [128] and synthesis of cytochrome c oxidase 2 (SCO2) [129]), whereas a great proportion of viable strains, surprisingly, exhibit no neuropathology (e.g., knockouts of ANT-1 [130], PPARγ [131], ERRα [132], and SURF1 [133]; Twinkle mutant 'Deletor' mice [134], and ΔmtDNA Mito-Mice [135]). To our knowledge, murine knockouts of AIF [136,137], SOD2 [138], thymidine phosphorylase and uridine phosphorylase (TP/UP) [139], and NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4) [140] are the only ones that display a neuropathology resembling that of human mitochondrial encephalopathies (Table 2).…”