AI Article Synopsis

  • Ischemia-reperfusion (IR) injury is a major cause of acute kidney injury (AKI) and is linked to succinate accumulation, which leads to harmful reactive oxygen species (ROS) and severe kidney damage.
  • Research on PDK4, a mitochondrial enzyme, shows that knocking it out or inhibiting it reduces IR-induced kidney damage by lowering succinate levels and ROS production during reperfusion.
  • The study concludes that targeting PDK4 could be an effective way to prevent kidney injury during IR events by minimizing succinate accumulation and protecting mitochondrial function.

Article Abstract

Ischemia-reperfusion (IR) injury, a leading cause of acute kidney injury (AKI), is still without effective therapies. Succinate accumulation during ischemia followed by its oxidation during reperfusion leads to excessive reactive oxygen species (ROS) and severe kidney damage. Consequently, the targeting of succinate accumulation may represent a rational approach to the prevention of IR-induced kidney injury. Since ROS are generated primarily in mitochondria, which are abundant in the proximal tubule of the kidney, we explored the role of pyruvate dehydrogenase kinase 4 (PDK4), a mitochondrial enzyme, in IR-induced kidney injury using proximal tubule cell-specific Pdk4 knockout (Pdk4) mice. Knockout or pharmacological inhibition of PDK4 ameliorated IR-induced kidney damage. Succinate accumulation during ischemia, which is responsible for mitochondrial ROS production during reperfusion, was reduced by PDK4 inhibition. PDK4 deficiency established conditions prior to ischemia resulting in less succinate accumulation, possibly because of a reduction in electron flow reversal in complex II, which provides electrons for the reduction of fumarate to succinate by succinate dehydrogenase during ischemia. The administration of dimethyl succinate, a cell-permeable form of succinate, attenuated the beneficial effects of PDK4 deficiency, suggesting that the kidney-protective effect is succinate-dependent. Finally, genetic or pharmacological inhibition of PDK4 prevented IR-induced mitochondrial damage in mice and normalized mitochondrial function in an in vitro model of IR injury. Thus, inhibition of PDK4 represents a novel means of preventing IR-induced kidney injury, and involves the inhibition of ROS-induced kidney toxicity through reduction in succinate accumulation and mitochondrial dysfunction.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2023.06.022DOI Listing

Publication Analysis

Top Keywords

succinate accumulation
24
kidney injury
16
ir-induced kidney
16
inhibition pdk4
16
accumulation ischemia
12
succinate
10
kidney
9
pdk4
9
pyruvate dehydrogenase
8
dehydrogenase kinase
8

Similar Publications

Unlabelled: Seed storability is a crucial agronomic trait and indispensable for the safe storage of rice seeds and grains. Nevertheless, the metabolite mechanisms governing rice seed storability under natural conditions are still poorly understood.

Methods: Therefore, the seed storage tolerance of global rice core germplasms stored for two years under natural aging conditions were identified, and two extreme groups with different seed storabilities from the rice group were analyzed using the UPLC-MS/MS metabolomic strategy.

View Article and Find Full Text PDF

The quality and flavor of Liuyang Douchi are usually closely related to the metabolites compostion. This work described the metabolic profiles of Liuyang douchi during fermentation. Obvious hydrolysis of carbohydrates, proteins and slight lipids degradation were observed.

View Article and Find Full Text PDF

Tumor and intratumoral pathogen cascade-targeting photothermal nanotherapeutics for boosted immunotherapy of colorectal cancer.

J Control Release

January 2025

State Key Laboratory of Separation Membranes and Membrane Processes & Key Laboratory of Hollow Fiber Membrane Materials and Membrane Processes (MOE) & Tianjin Key Laboratory of Hollow Fiber Membrane Materials and Processes, School of Materials Science and Engineering, Tiangong University, Tianjin 300387, China. Electronic address:

Clinical benefits of immunotherapy in colorectal cancer (CRC) are limited due to the low immunogenicity and immunosuppressive tumor microenvironment. Fusobacterium nucleatum (Fn) is discovered to colonize CRC tumors and dampen immunotherapy by fostering an immunosuppressive TME. Herein, a controllable "Shielding-deshielding" N-acetylgalactosamine (GalNAc)-derived photothermal nanotherapeutic is developed to mediate cascade targeting toward tumor and intratumoral Fn for enhanced photothermal-immunotherapy.

View Article and Find Full Text PDF

Waterlogging is a significant stressor for crops, particularly in lowland regions where soil conditions exacerbate the problem. Waterlogged roots experience hypoxia, disrupting oxidative phosphorylation and triggering metabolic reorganization to sustain energy production. Here, we investigated the metabolic aspects that differentiate two soybean sister lines contrasting for waterlogging tolerance.

View Article and Find Full Text PDF

In the context of organic farming, the introduction of a local product to wider markets and an evaluation of storage effects, metabolic and transcriptomic variations in two broccoli rabe genotypes from production cycles of two different years were studied by comparing florets of stored fresh (SF) and packaged (P) for 4 days with those harvested fresh from the field (H). Twenty-five hydrosoluble compounds, including amino acids, carbohydrates, and organic acids, were quantified by untargeted nuclear magnetic resonance (NMR). Principal component analysis produced a neat separation among the three commodity statuses with P being the most divergent and SF closer to H.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!