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

ABSTRACT: 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 extensive dysregulation of the mitochondrial SLC25 carrier family. The metabolite and lipid landscape were perturbed by severe hyperglycemia; 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 provides insights into altered substrate utilization and energy generation in the kidney early in diabetes, during moderate and severe hyperglycemia and has implications for therapeutic strategies aiming at the reinvigoration of mitochondrial function and signaling in diabetes.

ORGANISM(S): Rat Rattus Norvegicus

TISSUE(S): Kidney

DISEASE(S): Diabetes

SUBMITTER: Nikeisha Caruana

PROVIDER: ST002382 | MetabolomicsWorkbench | Wed Nov 09 00:00:00 GMT 2022

REPOSITORIES: MetabolomicsWorkbench

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Project description:Pre-existing and gestationally-developed diabetes mellitus during pregnancy have been linked to impaired metabolic function in the villous trophoblast layer of the placenta. These metabolic impairments have been thought to mediate an increased risk of early life metabolic disease development in the exposed offspring. Previous research using the BeWo trophoblast cell line has suggested that independently, hyperglycemia is an important modulator of placental metabolic function in diabetic pregnancies. However, the direct impacts of hyperglycemia on specific aspects of placental metabolic function known to be impaired in diabetic pregnancies including nutrient storage and mitochondrial respiration, are largely unknown. The current study, therefore, utilized functional readouts of metabolic enzyme activity and endpoint readouts of nutrient storage in conjunction with multi-omics analysis (transcriptomics and metabolomics) in BeWo trophoblasts cultured under hyperglycemia conditions (25 mM glucose) for 72 hours to further characterize the impacts of elevated glucose levels on placental metabolic function. While metabolic enzyme activities and mitochondrial oxidative respiratory function were not altered following 72 hours of hyperglycemia, increased triglyceride and glycogen nutrient stores were observed in the high-glucose exposed BeWo trophoblasts. We speculated that the increased nutrient stores serve to modulate intracellular glucose levels and may reduce the amount of glucose available for oxidation and subsequently protect trophoblast cells from mitochondrial damage during acute high glucose exposures. Additionally, hyperglycemic-culture conditions in BeWo trophoblasts were associated with an altered transcriptomic profile highlighted by altered mRNA expression of metabolic enzymes as well as with an altered metabolome profile highlighted by an intracellular accumulation of lactate, malonate, and riboflavin. Overall, the results demonstrate that exposure to excess glucose modulates placental metabolism and nutrient storage and highlights that increased glucose abundance is an important independent regulator of placental function in diabetic pregnancies.

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

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