Aging related impairment of brain microvascular bioenergetics involves oxidative phosphorylation and glycolytic pathways

Abstract

Mitochondrial and glycolytic energy pathways regulate the vascular functions. Aging impairs the cerebrovascular function and increases the risk of stroke and cognitive dysfunction. The goal of our study is to characterize the impact of aging on brain microvascular energetics. We measured the oxygen consumption and extracellular acidification rates of freshly isolated brain microvessels (BMVs) from young (2–4 months) and aged (20–22 months) C57Bl/6 male mice. Cellular ATP production in BMVs was predominantly dependent on oxidative phosphorylation (OXPHOS) with glucose as the preferred energy substrate. Aged BMVs exhibit lower ATP production rate with diminished OXPHOS and glycolytic rate accompanied by increased utilization of glutamine. Impairments of glycolysis displayed by aged BMVs included reduced compensatory glycolysis whereas impairments of mitochondrial respiration involved reduction of spare respiratory capacity and proton leak. Aged BMVs showed reduced levels of key glycolysis proteins including glucose transporter 1 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 but normal lactate dehydrogenase activity. Mitochondrial protein levels were mostly unchanged whereas citrate synthase activity was reduced, and glutamate dehydrogenase was increased in aged BMVs. Thus, for the first time, we identified the dominant role of mitochondria in bioenergetics of BMVs and the alterations of the energy pathways that make the aged BMVs vulnerable to injury.

Piezo1 channel activation stimulates ATP production through enhancing mitochondrial respiration and glycolysis in vascular endothelial cells

“…Recently, it was reported that oxidative phosphorylation also played an important role in endothelial cells. Sakamuri et al reported that cellular ATP production in isolated brain microvessels was predominantly dependent on oxidative phosphorylation (Sakamuri et al, 2022). Wilson et al reported that mitochondrial ATP generated in endothelial cells was necessary for calcium‐dependent, nitric oxide mediated endothelial control of vascular tone (Wilson et al, 2021).…”

Intermittent Cytomegalovirus Infection Alters Neurobiological Metabolism and Induces Cognitive Deficits in Mice

“…Age and senescence related decreases in glycolysis and OXPHOS have previously been reported in BMECs suggesting that MCMV infection may accelerate an aging phenotype relative to mock infected animals (Sakamuri et al, 2022). Uncoupling of the ETC may explain the increased proton leak and play a protective role by mitigating ROS production and therefore oxidative damage (Divakaruni and Brand, 2011).…”

Mitochondrial ATP Production is Required for Endothelial Cell Control of Vascular Tone

“…In this regard, some investigators have used metabolic flux analysis to show that isolated brain capillaries (composed mostly of ECs) primarily use oxidative phosphorylation. 89 RNA sequencing of freshly isolated single ECs is also increasingly being used, without a cell culture step, to characterize endothelial metabolic signatures. 90 , 91 Such studies reveal a diversity of metabolic profiles (mitochondrial and glycolytic) amongst ECs of various organs.…”