Abstract
As numerous complex pathologies stem from cellular energy dysfunction, we aimed to elucidate mitochondrial function and associated stress pathologies in kidney disease in a cohort of hemodialysis patients with end-stage kidney disease (ESKD). The bioenergetics study was conducted using peripheral blood mononuclear cells (PBMCs) of ESKD patients (n = 29) and healthy controls (no ESKD, n = 10). PBMCs were isolated from whole blood and seeded into assay plates to detect changes in oxidative phosphorylation and glycolysis. The bioenergetics analysis (i.e., mitochondrial stress test) was performed using Seahorse XFe24 flux analyzer. We observed significant reduction in mitochondrial respiration in patient PBMCs in terms of fundamental bioenergetics parameters such as basal respiration, ATP turnover, maximal respiration and spare respiratory capacity. These findings were correlated with the expression levels of proteins coordinating cellular energy status and regulating mitochondrial dynamics. Our data demonstrates an association between mitochondrial oxygen consumption of PBMCs and ESKD. AMPK activity, its downstream effector PGC-1α and mitochondrial fission/fusion proteins are partially responsible for the decrease in oxidative phosphorylation of PBMCs isolated from ESKD patients. We propose a link between mitochondrial dysfunction and ESKD and a role for mitochondria as a potential site for therapeutic interventions.
Highlights
Chronic kidney disease (CKD) is a debilitating condition that can lead to progressive loss of kidney function and patients being placed on renal replacement therapy [1]
We first established the “resting” oxygen consumption rate (OCR) (OCRinitial), which accounts for the basal rate of respiration in peripheral blood mononuclear cells (PBMCs) after removing the contribution from non-mitochondrial oxygen consumption (Figure 1B)
We found that PBMCs isolated from healthy individuals had a significantly higher basal
Summary
Chronic kidney disease (CKD) is a debilitating condition that can lead to progressive loss of kidney function and patients being placed on renal replacement therapy [1]. It is defined as a decreased glomerular filtration rate (GFR) of less than 60 ml/min/1.73 m2 for at least 3 months and classified into five stages based on the GFR [2]. CKD patients can progress to end stage kidney disease (ESKD) at stage 5, where GFR is less than 15 ml/min/1.73 m2. Altered mitochondrial bioenergetics is central to the development and progression of a wide range of human diseases, including kidney diseases [3,4,5]. Cells generate energy (in the form of ATP) necessary for cellular metabolism mainly through oxidative phosphorylation in mitochondria [6].
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