CoQ10 ameliorates mitochondrial dysfunction in diabetic nephropathy through mitophagy

in Journal of Endocrinology
Correspondence should be addressed to H Huang: huanghuiya1248@126.com
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The molecular signaling mechanisms of Coenzyme Q10 (CoQ10) in diabetic nephropathy (DN) remain poorly understood. We verified that mitochondrial abnormalities, like defective mitophagy, the generation of mitochondrial reactive oxygen species (mtROS) and the reduction of mitochondrial membrane potential, occurred in the glomerulus of db/db mice, accompanied by reduced PINK and parkin expression and increased apoptosis. These changes were partially reversed following oral administration of CoQ10. In inner fenestrated murine glomerular endothelial cells (mGECs), high glucose (HG) also resulted in deficient mitophagy, mitochondrial dysfunction and apoptosis, which were reversed by CoQ10. Mitophagy suppression mediated by Mdivi-1 or siPINK abrogated the renoprotective effects exerted by CoQ10, suggesting a beneficial role for CoQ10-restored mitophagy in DN. Mechanistically, CoQ10 restored the expression, activity and nuclear translocation of Nrf2 in HG-cultured mGECs. In addition, the reduced PINK and parkin expression observed in HG-cultured mGECs were partially elevated by CoQ10. CoQ10-mediated renoprotective effects were abrogated by the Nrf2 inhibitor ML385. When ML385 abolished mitophagy and the renoprotective effects exerted by CoQ10, mGECs could be rescued by treatment with mitoTEMPO, which is a mtROS-targeted antioxidant. These results suggest that CoQ10, as an effective antioxidant in mitochondria, exerts beneficial effects in DN via mitophagy by restoring Nrf2/ARE signaling. In summary, CoQ10-mediated mitophagy activation positively regulates DN through a mechanism involving mtROS, which influences the activation of the Nrf2/ARE pathway.

 

      Society for Endocrinology

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    CoQ10 restores the renal function impaired by diabetic nephropathy. (A) PAS staining in glomeruli from db/m + vehicle, db/db + vehicle and db/db + CoQ10 mice. (B) H&E staining in glomeruli from db/m + vehicle, db/db + vehicle and db/db + CoQ10 mice. (C) TUNEL assay in glomeruli from db/m + vehicle, db/db + vehicle and db/db + CoQ10 mice. The apoptotic cells were labeled with green, and nuclei were stained with DAPI (blue). (D) Left kidney weight changes in db/m, db/db and db/db mice receiving CoQ10 treatment for 8 weeks. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (E) Serum creatinine levels in db/m, db/db and db/db mice receiving CoQ10 treatment for 8 weeks. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (F) The quantitative analysis of TUNEL+ cells in (C) in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (G) Urinary Albumin to creatinine levels in db/m, db/db and db/db mice receiving CoQ10 treatment for 8 weeks. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (H) Blood glucose concentrations in db/m, db/db and db/db mice receiving CoQ10 treatment for 8 weeks. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (I) Tissue lysates of glomeruli were used to detect the c-Caspase 3, Bax and Bcl-2 protein levels by immunoblotting in db/m, db/db and db/db mice receiving CoQ10 treatment for 8 weeks. (J) The quantitative analysis of each immunoblots in (I). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (K) Cell lysates of each group (CON, HG, HG + CoQ10) were used to detect the c-Caspase 3, Bax and Bcl-2 protein levels by immunoblotting. (L) The quantitative analysis of each immunoblots in (K). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG. (M) Tissue lysates of glomeruli were used to detect the release of Cytochrome c from mitochondria into cytosol in db/m, db/db and db/db mice receiving CoQ10 treatment for 8 weeks. (N) Cell lysates of each group (CON, HG, HG + CoQ10) were used to detect the release of Cytochrome c from mitochondria into cytosol by immunoblotting. (O) The quantitative analysis of each immunoblots in (M). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (P) The quantitative analysis of each immunoblots in (N). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0578.

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    CoQ10 ameliorates DN-induced mitochondrial dysfunction both in vivo and in vitro. (A) mtDNA content and ATP production in db/m, db/db and db/db mice receiving CoQ10 treatment for 8 weeks. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (B) Effects of CoQ10 on mitoSOX in glomeruli. (C) The quantitative analysis of fluorescence intensity in (B), values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (D) SeaHorse XF24 Flux Analyses of OCR during a maximal electron flow test in mGECs of each group (CON, HG, HG + CoQ10). For electron flow, all data are expressed as median ± interquartile range. (E) Relative mtDNA content and ATP production in mGECs of each group (CON, HG, HG + CoQ10). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (F) Representative images of JC-1 fluorescence in mGECs of each group (CON, HG, HG + CoQ10). (G) Effects of CoQ10 on mitoSOX in mGECs. (H) The quantitative analysis of fluorescence intensity in (F), values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG. (I) Effects of CoQ10 on mitochondrial membrane potential in mGECs of each group (CON, HG, HG + CoQ10) measured using TMREfluorescence. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0578.

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    CoQ10 increases mitophagy in DN. (A) Representative images of LC3 (red) staining in glomeruli from db/m + vehicle, db/db + vehicle and db/db + CoQ10 mice. Glomeruli mitochondrial is labeled with TOM20 (green). (B) Glomerular endothelial mitochondrial lysates were used to detect the LC3, PINK, and parkin protein levels by immunoblotting in db/m, db/db and db/db mice receiving CoQ10 treatment for 8 weeks. (C) The quantitative analysis of each immunoblots in (B). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (D) mGECs mitochondrial lysates were used to detect the LC3, PINK, and parkin protein levels by immunoblotting of each group (CON, HG, HG + CoQ10). (E) The quantitative analysis of each immunoblots in (D). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0578.

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    The renoprotection in vivo exerted by CoQ10 requires PINK-related mitophagy. (A) PAS staining in glomeruli from the indicated groups. (B) H&E staining in glomeruli from the indicated groups. (C) TUNEL assay in glomeruli from the indicated groups. The apoptotic cells were labeled with green, and nuclei were stained with DAPI (blue). (D) MitoSOX staining in glomeruli from the indicated groups. (E) Left kidney weight changes in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle. (F) Serum creatinine levels in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle. (G) Albumin to creatinine levels in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle. (H) The quantitative analysis of TUNEL+ cells in (C) in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle. (I) Relative mtDNA content in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle. (J) Relative ATP production in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle. (K) The quantitative analysis of fluorescence intensity in (D), values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0578.

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    The renoprotection in vitro exerted by CoQ10 requires PINK-related mitophagy. (A) Representative images of JC-1 fluorescence in mGECs of each group (CON, HG, HG + CoQ10, HG + siPINK, HG + CoQ10 + siPINK). (B) MitoSOX staining in mGECs from the indicated groups. (C) TMRE fluorescence staining in mGECs from the indicated groups. (D) Relative mtDNA content in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG; & P < 0.05 vs HG + CoQ10. (E) Relative ATP production in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG; & P < 0.05 vs HG + CoQ10. (F) The quantitative analysis of fluorescence intensity in (B), values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG; & P < 0.05 vs HG + CoQ10. (G) Cell lysates of the indicated groups were used to detect the c-Caspase 3, Bax and Bcl-2 protein levels by immunoblotting. (H) The quantitative analysis of each immunoblots in (G). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG; & P < 0.05 vs HG + CoQ10. (I) Tissue lysates of glomeruli from the indicated groups were used to detect the c-Caspase 3, Bax and Bcl-2 protein levels by immunoblotting. (J) The quantitative analysis of each immunoblots in (I). Values displayed are means ± s.e.m. of six independent experiments. *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0578.

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    CoQ10 induces mitophagy by activating the Nrf2/ARE pathway. (A) Assessment of Nrf2/ARE reporter activity in mGECs from the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG. (B) Assessment of PGC-1α reporter activity in mGECs from the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG. (C) Assessment of SIRT1 reporter activity in mGECs from the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG. (D) Cell lysates of the indicated groups were used to detect the Nrf2, NQO-1 and HO-1 protein levels by immunoblotting. (E) The quantitative analysis of each immunoblots in (D). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG. (F) The quantitative analysis of the Nrf2 in (J). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (G) Tissue lysates of glomeruli were used to detect the Nrf2, NQO-1 and HO-1 protein levels by immunoblotting. (H) The quantitative analysis of each immunoblots in (G). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle. (I) The quantitative analysis of the Nrf2 in (K). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG. (J) Subcellular localization of endogenous Nrf2 in glomerulus from the indicated groups was measured by immunoblotting. (K) Subcellular localization of endogenous Nrf2 in mGECs from the indicated groups was measured by immunoblotting.

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    Nrf2/ARE is necessary for CoQ10-mediated mitophagy activation. (A) Mice glomerulus mitochondrial lysates were used to detect the LC3, PINK, and parkin protein levels from each group. (B) The quantitative analysis of each immunoblots in (A). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. (C) mGECs mitochondrial lysates were used to detect the LC3, PINK, and parkin protein levels by immunoblotting of each group. (D) The quantitative analysis of each immunoblots in (C). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG; & P < 0.05 vs HG + CoQ10; @ P < 0.05 vs HG + CoQ10 + siNrf2. (E) Representative images of LC3 (red) staining in glomeruli from the indicated groups. Glomeruli mitochondrial is labeled with TOM20 (green). A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0578.

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    CoQ10 treatment has no effect on mitophagy and Nrf2 signaling under basal conditions. (A) Representative images of LC3 (red) staining in glomeruli from the indicated groups. Glomeruli mitochondrial is labeled with TOM20 (green). (B) Glomerular endothelial mitochondrial lysates were used to detect the LC3, PINK, and parkin protein levels by immunoblotting in db/m mice receiving vehicle or CoQ10 treatment. (C) mGECs mitochondrial lysates were used to detect the LC3, PINK, and parkin protein levels by immunoblotting of each group (CON, CON + CoQ10). (D) Tissue lysates of glomeruli were used to detect the Nrf2, NQO-1 and HO-1 protein levels by immunoblotting. (E) Cell lysates of the indicated groups were used to detect the Nrf2, NQO-1 and HO-1 protein levels by immunoblotting. (F) Subcellular localization of endogenous Nrf2 in glomerulus from the indicated groups was measured by immunoblotting. (G) Subcellular localization of endogenous Nrf2 in mGECs from the indicated groups was measured by immunoblotting. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0578.

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    CoQ10 restores renal function and morphological changes via Nrf2/ARE. (A) PAS staining in glomeruli from the indicated groups. (B) H&E staining in glomeruli from the indicated groups. (C) TUNEL assay in glomeruli from the indicated groups. The apoptotic cells were labeled with green, and nuclei were stained with DAPI (blue). (D) MitoSOX staining in glomeruli from the indicated groups. (E) Left kidney weight changes in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. (F) Serum creatinine levels in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. (G) Albumin to creatinine levels in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. (H) The quantitative analysis of TUNEL+ cells in (C) in at least six separate fields, values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. (I) Relative mtDNA content in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. (J) Relative ATP production in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. (K) The quantitative analysis of fluorescence intensity in (D), values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0578.

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    CoQ10 restores renal function and morphological changes via Nrf2/ARE. (A) Representative images of JC-1 fluorescence in mGECs of each group. (B) MitoSOX staining in mGECs from the indicated groups. (C) TMRE fluorescence staining in mGECs from the indicated groups. (D)The quantitative analysis of fluorescence intensity in (B), values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG; & P < 0.05 vs HG + CoQ10; @ P < 0.05 vs HG + CoQ10 + siNrf2. (E) Cell lysates of the indicated groups were used to detect the c-Caspase 3, Bax and Bcl-2 protein levels by immunoblotting. (F) Tissue lysates of glomeruli from the indicated groups were used to detect the c-Caspase 3, Bax and Bcl-2 protein levels by immunoblotting. (G) Relative mtDNA content in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG; & P < 0.05 vs HG + CoQ10; @ P < 0.05 vs HG + CoQ10 + siNrf2. (H) Relative ATP production in the indicated groups. Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. (I) The quantitative analysis of each immunoblots in (E). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs CON; *P < 0.05 vs HG; & P < 0.05 vs HG + CoQ10; @ P < 0.05 vs HG + CoQ10 + siNrf2. (J) The quantitative analysis of each immunoblots in (F). Values displayed are means ± s.e.m. of six independent experiments. # P < 0.05 vs db/m + vehicle; *P < 0.05 vs db/db + vehicle; & P < 0.05 vs db/db + CoQ10 + vehicle; @ P < 0.05 vs db/db + CoQ10 + ML385. A full colour version of this figure is available at https://doi.org/10.1530/JOE-18-0578.

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