Indispensable role of mitochondria in maintaining the therapeutic potential of curcumin in acute kidney injury

Abstract

Acute kidney injury (AKI) is a serious disease for which effective therapeutic agents are required. The capacity of curcumin (CUR) to resolve renal inflammation/oxidative stress and mitochondrial damage has been reported, but crosstalk between these effects and the consequence of this crosstalk remain elusive. In this study, a hypoxia/reoxygenation (H/R)‐induced renal tubular epithelial cell (TEC) injury model and an ischaemia/reperfusion (I/R)‐induced mouse AKI model were treated with CUR with or without mitochondrial inhibitors (rotenone and FCCP) or siRNA targeting mitochondrial transcription factor A (TFAM). Changes in mitochondrial function, inflammation, the antioxidant system and related pathways were analysed. In vitro, CUR suppressed NFκB activation and cytokine production and induced NRF2/HO‐1 signalling in TECs under H/R conditions. CUR treatment also reduced mitochondrial ROS (mtROS) and mitochondrial fragmentation and enhanced mitochondrial biogenesis, TCA cycle activity and ATP synthesis in damaged TECs. However, the anti‐inflammatory and antioxidant effects of CUR in damaged TECs were markedly abolished upon mitochondrial disruption. In vivo, CUR treatment improved renal function and antioxidant protein (NRF2 and SOD2) expression and reduced oxidative stress (8‐OHdG), tubular apoptosis/death, cytokine release/macrophage infiltration and mitochondrial damage in the kidneys of AKI mice. In vitro, the anti‐inflammatory and antioxidant effects of CUR in damaged kidneys were impaired when mitochondrial function was disrupted. These results suggest mitochondrial damage is a driving factor of renal inflammation and redox imbalance. The therapeutic capacity of CUR in kidneys with AKI is primarily dependent on mitochondrial mechanisms; thus, CUR is a potential therapy for various diseases characterized by mitochondrial damage.

Curcumae Radix Decreases Neurodegenerative Markers through Glycolysis Decrease and TCA Cycle Activation

“…In the pathological conditions of Alzheimer's disease, tau destabilizes microtubules when excessively phosphorylated [66]. Since curcumin enhances energy and mitochondrial metabolism [67,68], the TCA cycle activation states might be represented by the Curcumae radix treatment. We used hTau23 Tg mice (24 weeks old), which showed high levels of tau phosphorylation with advanced age [69].…”

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases

“…In the kidney of lipopolysaccharide-treated animals, NDUFS8 decreased and then led to decreased fatty acids oxidation following lipopolysaccharide treatment [136]. Because of the mitochondrial structural disorder after acute kidney injury, the level of NDUFS8 was down about 50%, which was ameliorated by some materials, such as mitochondria-targeted antioxidant Mito-2,2,6,6-tetramethylpiperidine-N-oxyl by injectable self-assembling peptide hydrogel, a novel cyclic helix B peptide, 5-methoxyindole-2-carboxylic acid, and curcumin [137][138][139][140]. Interestingly, NDUFS8 played a role in the process that perfusion of isolated rat kidneys with mesenchymal stromal cells/extracellular vesicles prevents ischemic damage, creating a possible application of NDUFS8 in organ transplantation [141].…”