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

VL - 61

SP - 215

EP - 224

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

ER -