TY - JOUR
T1 - Initial brain aging
T2 - heterogeneity of mitochondrial size is associated with decline in complex I-linked respiration in cortex and hippocampus
AU - Thomsen, Kirsten
AU - Yokota, Takashi
AU - Hasan-Olive, Md Mahdi
AU - Sherazi, Niloofar
AU - Fakouri, Nima Borhan
AU - Desler, Claus
AU - Regnell, Christine Elisabeth
AU - Larsen, Steen
AU - Rasmussen, Lene Juel
AU - Dela, Flemming
AU - Bergersen, Linda Hildegard
AU - Lauritzen, Martin
PY - 2018
Y1 - 2018
N2 - Brain aging is accompanied by declining mitochondrial respiration. We hypothesized that mitochondrial morphology and dynamics would reflect this decline. Using hippocampus and frontal cortex of a segmental progeroid mouse model lacking Cockayne syndrome protein B (CSBm/m) and C57Bl/6 (WT) controls and comparing young (2–5 months) to middle-aged mice (13–14 months), we found that complex I-linked state 3 respiration (CI) was reduced at middle age in CSBm/m hippocampus, but not in CSBm/m cortex or WT brain. In hippocampus of both genotypes, mitochondrial size heterogeneity increased with age. Notably, an inverse correlation between heterogeneity and CI was found in both genotypes, indicating that heterogeneity reflects mitochondrial dysfunction. The ratio between fission and fusion gene expression reflected age-related alterations in mitochondrial morphology but not heterogeneity. Mitochondrial DNA content was lower, and hypoxia-induced factor 1α mRNA was greater at both ages in CSBm/m compared to WT brain. Our findings show that decreased CI and increased mitochondrial size heterogeneity are highly associated and point to declining mitochondrial quality control as an initial event in brain aging.
AB - Brain aging is accompanied by declining mitochondrial respiration. We hypothesized that mitochondrial morphology and dynamics would reflect this decline. Using hippocampus and frontal cortex of a segmental progeroid mouse model lacking Cockayne syndrome protein B (CSBm/m) and C57Bl/6 (WT) controls and comparing young (2–5 months) to middle-aged mice (13–14 months), we found that complex I-linked state 3 respiration (CI) was reduced at middle age in CSBm/m hippocampus, but not in CSBm/m cortex or WT brain. In hippocampus of both genotypes, mitochondrial size heterogeneity increased with age. Notably, an inverse correlation between heterogeneity and CI was found in both genotypes, indicating that heterogeneity reflects mitochondrial dysfunction. The ratio between fission and fusion gene expression reflected age-related alterations in mitochondrial morphology but not heterogeneity. Mitochondrial DNA content was lower, and hypoxia-induced factor 1α mRNA was greater at both ages in CSBm/m compared to WT brain. Our findings show that decreased CI and increased mitochondrial size heterogeneity are highly associated and point to declining mitochondrial quality control as an initial event in brain aging.
KW - Brain aging
KW - Cockayne syndrome B
KW - Complex I-linked respiration
KW - Mitochondrial dynamics
KW - Mitochondrial morphology
KW - mtDNA copy numbers
U2 - 10.1016/j.neurobiolaging.2017.08.004
DO - 10.1016/j.neurobiolaging.2017.08.004
M3 - Journal article
C2 - 29031832
AN - SCOPUS:85031127310
SN - 0197-4580
VL - 61
SP - 215
EP - 224
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -