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ALCAT1-mediated abnormal cardiolipin remodelling promotes mitochondrial injury in podocytes in diabetic kidney disease
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study examined ALCAT1-mediated cardiolipin (CL) remodelling in diabetic kidney disease (DKD), using human glomerular tissue from DKD patients, db/db mouse kidneys, and cultured podocytes stimulated with high glucose. The abstract reports increased oxidized cardiolipin (ox-CL) and mitochondrial damage alongside increased ALCAT1 expression in glomeruli from DKD patients, with similar findings in db/db mouse kidneys and high-glucose-stimulated podocytes. ALCAT1 deficiency prevented high-glucose-induced ox-CL production and mitochondrial damage in podocytes, while ALCAT1 upregulation increased ox-CL levels and mitochondrial dysfunction. Treatment with the cardiolipin antioxidant SS-31 reduced mitochondrial dysfunction and cell injury and partly reversed damage caused by ALCAT1 overexpression; the authors describe ALCAT1 as mediating regulators of mitochondrial dynamics and mitophagy through the AMPK pathway.
Abstract
Cardiolipin (CL) plays a critical role in maintaining mitochondrial membrane integrity and overall mitochondrial homeostasis. Recent studies have suggested that mitochondrial damage resulting from abnormal cardiolipin remodelling is associated with the pathogenesis of diabetic kidney disease (DKD). Acyl-coenzyme A:lyso-cardiolipin acyltransferase-1 (ALCAT1) was confirmed to be involved in the progression of Parkinson's disease, diet-induced obesity and other ageing-related diseases by regulating pathological cardiolipin remodelling. Thus, the purpose of this investigation was to determine the role of ALCAT1-mediated CL remodelling in DKD and to explore the potential underlying mechanism. In vivo study, the mitochondrial structure was examined by transmission electron microscopy (TEM). The colocalization of ALCAT1 and synaptopodin was evaluated by double immunolabelling. Western blotting (WB) was performed to assess ALCAT1 expression in glomeruli. Lipidomics analysis was conducted to evaluate the composition of reconstructed cardiolipins. In vitro study, the lipidomics, TEM and WB analyses were similar to those in vivo. Mitochondrial function was evaluated by measuring the mitochondrial membrane potential (MMP) and the production of ATP and ROS. Here, we showed that increased oxidized cardiolipin (ox-CL) and significant mitochondrial damage were accompanied by increased ALCAT1 expression in the glomeruli of patients with DKD. Similar results were found in db/db mouse kidneys and in cultured podocytes stimulated with high glucose (HG). ALCAT1 deficiency effectively prevented HG-induced ox-CL production and mitochondrial damage in podocytes. In contrast, ALCAT1 upregulation enhanced ox-CL levels and podocyte mitochondrial dysfunction. Moreover, treatment with the cardiolipin antioxidant SS-31 markedly inhibited mitochondrial dysfunction and cell injury, and SS-31 treatment partly reversed the damage mediated by ALCAT1 overexpression. We further found that ALCAT1 could mediate the key regulators of mitochondrial dynamics and mitophagy through the AMPK pathway. Collectively, our studies demonstrated that ALCAT1-mediated cardiolipin remodelling played a crucial role in DKD, which might provide new insights for DKD treatment. Video Abstract.
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