We examined the effects of empagliflozin, a selective inhibitor of Na⁺-glucose cotransporter 2, on mitochondrial quality control and autophagy in renal tubular cells in a diabetic environment in vivo and in vitro. Human renal proximal tubular cells (hRPTCs) were incubated under high-glucose conditions. Diabetes was induced with streptozotocin in male C57BL/6J mice. Improvements in mitochondrial biogenesis and balanced fusion-fission protein expression were noted in hRPTCs after treatment with empagliflozin in high-glucose media. Empagliflozin also increased autophagic activities in renal tubular cells in the high-glucose environment, which was accompanied with mammalian target of rapamycin inhibition. Moreover, reduced mitochondrial reactive oxygen species production and decreased apoptotic and fibrotic protein expression were observed in hRPTCs after treatment with empagliflozin, even in the hyperglycemic circumstance. Importantly, empagliflozin restored AMP-activated protein kinase-α phosphorylation and normalized levels of AMP-to-ATP ratios in hRPTCs subjected to a high-glucose environment, which suggests the way that empagliflozin is involved in mitochondrial quality control. Empagliflozin effectively suppressed Na⁺-glucose cotransporter 2 expression and ameliorated renal morphological changes in the kidneys of streptozotocin-induced diabetic mice. Electron microscopy analysis showed that mitochondrial fragmentation was decreased and 8-hydroxy-2′-deoxyguanosine content was low in renal tubular cells of empagliflozin treatment groups compared with those of the diabetic control group. We suggest one mechanism related to the renoprotective actions of empagliflozin, which reverse mitochondrial dynamics and autophagy.

Osteoporosis, characterized by low bone mass and a disruption of bone microarchitecture, is traditionally treated using drugs or lifestyle modifications. Recently, several preclinical and clinical studies have investigated the effects of selenium on bone health, although the results are controversial. Selenium, an important trace element, is required for selenoprotein synthesis and acts crucially for proper growth and skeletal development. However, the intake of an optimum amount of selenium is critical, as both selenium deficiency and toxicity are hazardous for health. In this review, we have systematically analyzed the existing literature in this field to determine whether dietary or serum selenium concentrations are associated with bone health. In addition, the mode of administration of selenium as a supplement for treating bone disease is important. We have also highlighted the importance of using green-synthesized selenium nanoparticles as therapeutics for bone disease. Novel nanobiotechnology will be a bridgehead for clinical applications of trace elements and natural products.

Jeong HY, et al. Electrolyte Blood Press. 2017 Sep;15(1):1-11. https://doi.org/10.5049/EBP.2017.15.1.1

Mitochondrial dysfunction is considered to be an important mediator of the pro‐aging process in chronic kidney disease, which is continuously increasing worldwide. Although PTEN‐induced kinase 1 (PINK1) regulates mitochondrial function, its role in renal aging remains unclear. We investigated the association between PINK1 and renal aging, especially through the cGAS‐STING pathway, which is known to result in an inflammatory phenotype. Pink1 knockout (Pink1^−/−) C57BL/6 mice and senescence‐induced renal tubular epithelial cells (HKC‐8) treated with H₂O₂ were used as the renal aging models. Extensive analyses at transcriptomic‐metabolic levels have explored changes in mitochondrial function in PINK1 deficiency. To investigate whether PINK1 deficiency affects renal aging through the cGAS‐STING pathway, we explored their expression levels in PINK1 knockout mice and senescence‐induced HKC‐8 cells. PINK1 deficiency enhances kidney fibrosis and tubular injury, and increases senescence and the senescence‐associated secretory phenotype (SASP). These phenomena were most apparent in the 24‐month‐old Pink1^−/− mice and HKC‐8 cells treated with PINK1 siRNA and H₂O₂. Gene expression analysis using RNA sequencing showed that PINK1 deficiency is associated with increased inflammatory responses, and transcriptomic and metabolomic analyses suggested that PINK1 deficiency is related to mitochondrial metabolic dysregulation. Activation of cGAS‐STING was prominent in the 24‐month‐old Pink1^−/− mice. The expression of SASPs was most noticeable in senescence‐induced HKC‐8 cells and was attenuated by the STING inhibitor, H151. PINK1 is associated with renal aging, and mitochondrial dysregulation by PINK1 deficiency might stimulate the cGAS‐STING pathway, eventually leading to senescence‐related inflammatory responses.

The intervertebral disc (IVD) is a complex joint structure comprising three primary components—namely, nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplate (CEP). The IVD retrieves oxygen from the surrounding vertebral body through CEP by diffusion and likely generates ATP via anaerobic glycolysis. IVD degeneration is characterized by a cascade of cellular, compositional, structural changes. With advanced age, pronounced changes occur in the composition of the disc extracellular matrix (ECM). NP and AF cells in the IVD possess poor regenerative capacity compared with that of other tissues. Hypoxia-inducible factor (HIF) is a master transcription factor that initiates a coordinated cellular cascade in response to a low oxygen tension environment, including the regulation of numerous enzymes in response to hypoxia. HIF-1α is essential for NP development and homeostasis and is involved in various processes of IVD degeneration process, promotes ECM in NP, maintains the metabolic activities of NP, and regulates dystrophic mineralization of NP, as well as angiogenesis, autophagy, and apoptosis during IVD degeneration. HIF-1α may, therefore, represent a diagnostic tool for early IVD degeneration and a therapeutic target for inhibiting IVD degeneration

Purpose.In this study, we investigated the effect of PGC1αactivators on mitochondrial fusion, fission, and autophagic quality control in renal tubular cells in a diabetic environment in vivo and in vitro. We also examined whether the upregulation of PGC1αattenuates diabetic tubulopathy by normalizing mitochondrial homeostasis.Methods. HKC8 cells were subjected to high-glucose conditions (30 mM D-glucose). Diabetes was induced with streptozotocin (STZ, 50 mg/kg i.p. for 5 days) in male C57/BL6J mice. AICAR or metformin was used as a PGC1αactivator.Results.Treatment with the PGC1αactivators AICAR and metformin improved functional mitochondrial mass in HKC8 cells in high-glucose conditions. Moreover, in renal proximal tubular cells, increased PGC1αactivity correlated with the reversal of changes in Drp1, Mfn1, and LC3-II protein expression in a high-glucose environment. Normalized mitochondrial life cycles resulted in low ROS production and reduced apoptosis. AICAR and metformin treatment effectively mitigated albuminuria and renal histopathology and decreased the expression of TGFβ1 andαSMA in the kidneys of diabetic mice.Conclusions. Our results demonstrate that increases in PGC1αactivity improve diabetic tubulopathy by modulating mitochondrial dynamics and autophagy.