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Reduced adolescent-age spatial learning ability associated with elevated juvenile-age superoxide levels in complex I mouse mutants.

Mayer J, Reichart G, Tokay T, Lange F, Baltrusch S, Junghanss C, Wolkenhauer O, Jaster R, Kunz M, Tiedge M, Ibrahim S, Fuellen G, Köhling R - PLoS ONE (2015)

Bottom Line: Large-scale, heteroplasmic and generally pathogenic mtDNA defects (as induced by defective mitochondrial DNA polymerase, clonal mutations or DNA deletions) are known to negatively impact on life span and can result in apoptosis and tissue loss in, e.g., skeletal muscle or reduce learning abilities.A point mutation in complex III goes along with only a mild and non-significant negative effect on cognitive performance and no significant changes in ROS production.These findings suggest to also consider the ontogenetic development of phenotypes when studying mtDNA mutations and highlights a possible impact of complex I dysfunction on the emergence of neurological deficits.

View Article: PubMed Central - PubMed

Affiliation: Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, Germany.

ABSTRACT
Large-scale, heteroplasmic and generally pathogenic mtDNA defects (as induced by defective mitochondrial DNA polymerase, clonal mutations or DNA deletions) are known to negatively impact on life span and can result in apoptosis and tissue loss in, e.g., skeletal muscle or reduce learning abilities. The functional impact of homoplasmic specific mtDNA point mutations, e.g., in genes coding for the electron transport chain, however, remains a matter of debate. The present study contributes to this discussion and provides evidence that a single point mutation in complex I of the respiratory chain is associated with impairment of spatial navigation in adolescent (6-month-old) mice, i.e., reduced performance in the Morris Water Maze, which goes along with increased production of reactive oxygen species (ROS) in juvenile mice (3 months) but not at the age of phenotype expression. A point mutation in complex III goes along with only a mild and non-significant negative effect on cognitive performance and no significant changes in ROS production. These findings suggest to also consider the ontogenetic development of phenotypes when studying mtDNA mutations and highlights a possible impact of complex I dysfunction on the emergence of neurological deficits.

No MeSH data available.


Mitochondrial superoxide levels in the hippocampus of 6-month-old mice.Mitochondrial superoxide production in hippocampal slices (400 μm) was stained employing MitoSOX Red solution (shown in red color). Nuclei were counterstained with DAPI (shown in blue). (A) Bar graphs show comparison of mitochondrial superoxide levels between control strains (BL6 and mtAKR) and conplastic mutant strains (mtALR and mt129S1). Each bar represents mean fluorescence intensity (MFI) of MitoSOX Red as percentage to MFI of DAPI. All data consist of n = 5. (*p < 0.05). (B) Fluorescence microscopy of pyramidal cells from CA1 region of BL6 (B1), mtAKR (B2), mtALR (B3) and mt129S1 (B4). Pictures were taken with 120x magnification.
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pone.0123863.g003: Mitochondrial superoxide levels in the hippocampus of 6-month-old mice.Mitochondrial superoxide production in hippocampal slices (400 μm) was stained employing MitoSOX Red solution (shown in red color). Nuclei were counterstained with DAPI (shown in blue). (A) Bar graphs show comparison of mitochondrial superoxide levels between control strains (BL6 and mtAKR) and conplastic mutant strains (mtALR and mt129S1). Each bar represents mean fluorescence intensity (MFI) of MitoSOX Red as percentage to MFI of DAPI. All data consist of n = 5. (*p < 0.05). (B) Fluorescence microscopy of pyramidal cells from CA1 region of BL6 (B1), mtAKR (B2), mtALR (B3) and mt129S1 (B4). Pictures were taken with 120x magnification.

Mentions: We next hypothesized that mtDNA alterations of the two mutant strains would be associated with changes of ROS production. We therefore quantified mitochondrial superoxide by fluorescence microscopy of MitoSOX staining, first in age-matched (6 month-old), adolescent mice. The conplastic strain mtALR did not show significantly different superoxide levels compared to either of the controls (Fig 3A), and in particular not to the mtAKR strain. Indeed, the BL6 control strain displayed the lowest levels (95 ± 4.4%), while the strains based on the nt9821 9 alanine repeat background had higher levels, with the control strain mtAKR unexpectedly showing the highest superoxide levels (110 ± 4.1%) in this age group, followed by mtALR (106 ± 1.8%) and mt129S1 (98 ± 21.6)—the latter even being significantly different (p = 0.032).


Reduced adolescent-age spatial learning ability associated with elevated juvenile-age superoxide levels in complex I mouse mutants.

Mayer J, Reichart G, Tokay T, Lange F, Baltrusch S, Junghanss C, Wolkenhauer O, Jaster R, Kunz M, Tiedge M, Ibrahim S, Fuellen G, Köhling R - PLoS ONE (2015)

Mitochondrial superoxide levels in the hippocampus of 6-month-old mice.Mitochondrial superoxide production in hippocampal slices (400 μm) was stained employing MitoSOX Red solution (shown in red color). Nuclei were counterstained with DAPI (shown in blue). (A) Bar graphs show comparison of mitochondrial superoxide levels between control strains (BL6 and mtAKR) and conplastic mutant strains (mtALR and mt129S1). Each bar represents mean fluorescence intensity (MFI) of MitoSOX Red as percentage to MFI of DAPI. All data consist of n = 5. (*p < 0.05). (B) Fluorescence microscopy of pyramidal cells from CA1 region of BL6 (B1), mtAKR (B2), mtALR (B3) and mt129S1 (B4). Pictures were taken with 120x magnification.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390344&req=5

pone.0123863.g003: Mitochondrial superoxide levels in the hippocampus of 6-month-old mice.Mitochondrial superoxide production in hippocampal slices (400 μm) was stained employing MitoSOX Red solution (shown in red color). Nuclei were counterstained with DAPI (shown in blue). (A) Bar graphs show comparison of mitochondrial superoxide levels between control strains (BL6 and mtAKR) and conplastic mutant strains (mtALR and mt129S1). Each bar represents mean fluorescence intensity (MFI) of MitoSOX Red as percentage to MFI of DAPI. All data consist of n = 5. (*p < 0.05). (B) Fluorescence microscopy of pyramidal cells from CA1 region of BL6 (B1), mtAKR (B2), mtALR (B3) and mt129S1 (B4). Pictures were taken with 120x magnification.
Mentions: We next hypothesized that mtDNA alterations of the two mutant strains would be associated with changes of ROS production. We therefore quantified mitochondrial superoxide by fluorescence microscopy of MitoSOX staining, first in age-matched (6 month-old), adolescent mice. The conplastic strain mtALR did not show significantly different superoxide levels compared to either of the controls (Fig 3A), and in particular not to the mtAKR strain. Indeed, the BL6 control strain displayed the lowest levels (95 ± 4.4%), while the strains based on the nt9821 9 alanine repeat background had higher levels, with the control strain mtAKR unexpectedly showing the highest superoxide levels (110 ± 4.1%) in this age group, followed by mtALR (106 ± 1.8%) and mt129S1 (98 ± 21.6)—the latter even being significantly different (p = 0.032).

Bottom Line: Large-scale, heteroplasmic and generally pathogenic mtDNA defects (as induced by defective mitochondrial DNA polymerase, clonal mutations or DNA deletions) are known to negatively impact on life span and can result in apoptosis and tissue loss in, e.g., skeletal muscle or reduce learning abilities.A point mutation in complex III goes along with only a mild and non-significant negative effect on cognitive performance and no significant changes in ROS production.These findings suggest to also consider the ontogenetic development of phenotypes when studying mtDNA mutations and highlights a possible impact of complex I dysfunction on the emergence of neurological deficits.

View Article: PubMed Central - PubMed

Affiliation: Oscar-Langendorff-Institute of Physiology, Rostock University Medical Center, Rostock, Germany.

ABSTRACT
Large-scale, heteroplasmic and generally pathogenic mtDNA defects (as induced by defective mitochondrial DNA polymerase, clonal mutations or DNA deletions) are known to negatively impact on life span and can result in apoptosis and tissue loss in, e.g., skeletal muscle or reduce learning abilities. The functional impact of homoplasmic specific mtDNA point mutations, e.g., in genes coding for the electron transport chain, however, remains a matter of debate. The present study contributes to this discussion and provides evidence that a single point mutation in complex I of the respiratory chain is associated with impairment of spatial navigation in adolescent (6-month-old) mice, i.e., reduced performance in the Morris Water Maze, which goes along with increased production of reactive oxygen species (ROS) in juvenile mice (3 months) but not at the age of phenotype expression. A point mutation in complex III goes along with only a mild and non-significant negative effect on cognitive performance and no significant changes in ROS production. These findings suggest to also consider the ontogenetic development of phenotypes when studying mtDNA mutations and highlights a possible impact of complex I dysfunction on the emergence of neurological deficits.

No MeSH data available.