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Glycolytic and Oxidative Phosphorylation Defects Precede the Development of Senescence in Primary Human Brain Microvascular Endothelial Cells

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Abstract

Alterations of mitochondrial and glycolytic energy pathways related to aging could contribute to cerebrovascular dysfunction. We studied the impact of aging on energetics of primary human brain microvascular endothelial cells (HBMECs) by comparing the young (passages 7–9), pre-senescent (passages 13–15), and senescent (passages 20–21) cells. Pre-senescent HBMECs displayed decreased telomere length and undetectable telomerase activity although markers of senescence were unaffected. Bioenergetics in HBMECs were determined by measuring the oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Cellular ATP production in young HBMECs was predominantly dependent on glycolysis with glutamine as the preferred fuel for mitochondrial oxidative phosphorylation (OXPHOS). In contrast, pre-senescent HBMECs displayed equal contribution to ATP production rate from glycolysis and OXPHOS with equal utilization of glutamine, glucose, and fatty acids as mitofuels. Compared to young, pre-senescent HBMECs showed a lower overall ATP production rate that was characterized by diminished contribution from glycolysis. Impairments of glycolysis displayed by pre-senescent cells included reduced basal glycolysis, compensatory glycolysis, and non-glycolytic acidification. Furthermore, impairments of mitochondrial respiration in pre-senescent cells involved the reduction of maximal respiration and spare respiratory capacity but intact basal and ATP production-related OCR. Proton leak and non-mitochondrial respiration, however, were unchanged in the pre-senescent HBMECs. HBMECS at passages 20–21 displayed expression of senescence markers and continued similar defects in glycolysis and worsened OXPHOS. Thus, for the first time, we characterized the bioenergetics of pre-senescent HBMECs comprehensively to identify the alterations of the energy pathways that could contribute to aging.

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Acknowledgements

We thank Ms. Sufen Zheng for her technical help with the studies.

Funding

This research project was supported by the National Institutes of Health: National Institute of Neurological Disorders and Stroke (NS094834 and NS114286—P.V. Katakam; NS114286 – R. Mostany; NS099539 – X. Wang), National Institute on Aging (AG047296 – R. Mostany; AG-063345 – D. Busija; AG074489 – P.V. Katakam and R. Mostany), National Heart, Lung, Blood Institute (HL093554 – D. Busija; HL133619 – S. Lindsey), and National Institute of General Medical Sciences (NS094834—P.V. Katakam). In addition, the study was supported by American Heart Association (National Center Scientist Development Grant, 14SDG20490359—P.V. Katakam; Greater Southeast Affiliate Predoctoral Fellowship Award, 16PRE27790122—V.N. Sure; Predoctoral Fellowship Award, 20PRE35211153—W.R. Evans. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Pharmacology, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA, 70112, USA

    Siva S. V. P. Sakamuri, Venkata N. Sure, Lahari Kolli, Wesley R. Evans, Jared A. Sperling, David W. Busija, Sarah H. Lindsey, Ricardo Mostany & Prasad V. G. Katakam

  2. Neuroscience Program, Tulane Brain Institute, Tulane University, 200 Flower Hall, New Orleans, LA, 70118, USA

    Ning Liu, Wesley R. Evans, David W. Busija, Xiaoying Wang, Sarah H. Lindsey, Ricardo Mostany & Prasad V. G. Katakam

  3. Clinical Neuroscience Research Center, 131 S. Robertson, Suite 1300, New Orleans, LA, 70112, USA

    Ning Liu, Xiaoying Wang & Prasad V. G. Katakam

  4. J. Clayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA

    Walter L. Murfee

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  1. Siva S. V. P. Sakamuri
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Sakamuri, S.S.V.P., Sure, V.N., Kolli, L. et al. Glycolytic and Oxidative Phosphorylation Defects Precede the Development of Senescence in Primary Human Brain Microvascular Endothelial Cells. GeroScience 44, 1975–1994 (2022). https://doi.org/10.1007/s11357-022-00550-2

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