Biology subjects

Cooper, M. E.

Publications and source records attributed to Cooper, M. E..

3 recordsLinked to original sources

bioRxiv2026

Bioenergetic profiling of fresh human kidney tissue reveals compensatory metabolic adaptation and intrinsic mitochondrial dysfunction in diabetes

The kidney is a highly energetic organ, requiring substantial ATP production through mitochondrial oxidative phosphorylation to support tubular reabsorption. Metabolic reprogramming and impaired mitochondrial function are implicated in diabetic kidney disease, yet direct assessment of mitochondrial respiratory flux in the human kidney has been constrained by limited access to freshly obtained tissue. Consequently, much of the evidence supporting altered renal mitochondrial function in diabetes derives from animal models that do not fully recapitulate the human condition. We established a workflow for real-time bioenergetic profiling of fresh kidney cortex obtained during nephrectomy from living individuals with diabetes and preserved kidney function. Mitochondrial respiration, electron transport system activity and tubular mitochondrial morphology were compared with age- and sex-matched, histopathologically normal non-diabetic controls. High-resolution respirometry revealed increased mitochondrial respiratory flux in permeabilised diabetic kidney cortex. In contrast, mitochondria isolated from the same tissue exhibited reduced respiratory capacity and impaired complex I activity. Quantitative analysis of tubular cells demonstrated increased mitochondrial volume density together with greater mitochondrial fragmentation in diabetes. These findings reveal that the human kidney undergoes substantial metabolic adaptation early in diabetes, before measurable loss of kidney function. Increased tissue-level respiratory flux despite intrinsic mitochondrial impairment suggests that expansion and remodelling of the mitochondrial network may initially compensate for reduced organelle efficiency and sustain the kidneys high energetic demands. This compensatory state may, however, increase metabolic stress and vulnerability to subsequent kidney injury. To our knowledge, this study provides the first direct tissue-level functional evidence that mitochondrial metabolism is reprogrammed in the human kidney in diabetes before measurable kidney dysfunction develops. It defines an early bioenergetic signature characterised by tissue hypermetabolism despite impaired mitochondria-specific respiratory capacity, challenging the concept that diabetes produces a uniform decline in renal mitochondrial function. Failure to sustain this adaptive state may represent a critical transition towards diabetic kidney disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/740003v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@101eb51org.highwire.dtl.DTLVardef@100187corg.highwire.dtl.DTLVardef@1478af2org.highwire.dtl.DTLVardef@1f31fc1_HPS_FORMAT_FIGEXP M_FIG C_FIG One Sentence SummaryDiabetes drives early metabolic reprogramming of the human kidney before measurable kidney dysfunction

pathology↗

bioRxiv2023

Deep multi-omic profiling reveals extensive mitochondrial remodeling driven by glycemia in early diabetic kidney disease

Changes in mitochondrial energy metabolism are thought to be central to the development of diabetic kidney disease (DKD); however, whether this response is explicitly driven by systemic glucose concentrations remains unknown. Here, we show that titrating blood glucose concentrations in vivo directly impacts mitochondrial morphology and bioenergetics and remodels the mitochondrial proteome in the kidney in early DKD. Mitoproteomic analysis revealed profound metabolic disturbances induced by severe hyperglycemia, including upregulation of enzymes involved in the TCA cycle and fatty acid metabolism, enhanced ketogenesis as well as dysregulation of the mitochondrial SLC25 carrier family. Untargeted metabolomics and lipidomics confirmed the enrichment of TCA cycle metabolites, an increase in triglyceride concentrations, and extensive and specific cardiolipin remodeling. Lowering blood glucose to moderate hyperglycemia stabilized all three omic landscapes, partially prevented changes in mitochondrial morphology and bioenergetics, and improved kidney injury. This study demonstrates altered substrate utilization and energy generation in the kidney early in diabetes, during moderate and severe hyperglycemia and provides new insights into kidney metabolism, which has implications for therapeutic strategies aiming at the reinvigoration of mitochondrial function and signaling in diabetes.

cell biology↗

bioRxiv2019

Nuclear Expression and DNA Binding Capacity of Receptor for Advanced Glycation End Products in Renal Tissue

The AGER gene encodes for a number of RAGE isoforms, with the membrane bound signal transduction and \"decoy\" circulating soluble RAGE being the best characterised. Here we demonstrate a novel nuclear isoform of RAGE in mice and human kidney cortex which by cell and size fractionation we determined to be approximately 37kda. This nuclear RAGE isoform is functional and binds to DNA sequences within the upstream 5 promoter region of its own gene, AGER. This binding was shown to be abrogated by mutating the DNA consensus binding sequences during electromobility shift assay (EMSA) and was independent of NF-{square}B or AP-1 binding. Cotransfection of expression constructs encoding various RAGE isoforms along with AGER gene promoter reporter-plasmids identified that the most likely source of the nuclear isoform of RAGE was a cleavage product of the nt-RAGE isoform. In obese mice with impaired kidney function, there was increased binding of nuclear RAGE within the A. Region of ager gene promoter with corresponding increases in membrane bound RAGE in renal cells. These findings were reproduced in vitro using proximal tubule cells. Hence, we postulate that RAGE expression is in part, self-regulated by the binding of a nuclear RAGE isoform to the promoter of the AGER gene (encoding RAGE) in the kidney. We also suggest that this RAGE self-regulation is altered under pathological conditions and this may have implications for chronic kidney disease.

molecular biology↗