A mitochondrial-targeted peptide ameliorated podocyte apoptosis through a HOCl-alb-enhanced and mitochondria-dependent signalling pathway in diabetic rats and in vitro

Abstract

Mitochondria play important roles in the development of diabetic kidney disease (DKD). The SS peptide is a tetrapeptide that is located and accumulated in the inner mitochondrial membrane; it reduces reactive oxygen species (ROS) and prevents mitochondrial dysfunction. Podocytes are key cellular components in DKD progression. However, whether the SS peptide can exert renal protection through podocytes and the mechanism involved are unknown. In the present study, we explored the mechanisms of the SS peptide on podocyte injury in vivo and in vitro. Compared with the control group, the glomerular podocyte number and expression of WT1 were significantly reduced and TUNEL-positive podocytes were significantly increased in renal tissues in the diabetic rat. These effects were further exacerbated by hypochlorite-modified albumin (HOCl-alb) challenge but prevented by SS-31. In vitro, SS-31 blocked apoptosis in podocyte cell line induced by HOCl-alb. SS-31 prevented oxidative stress and mitochondria-dependent apoptosis signalling by HOCl-alb in vivo and in vitro, as evidenced by the release of cytochrome c (cyt c), binding of apoptosis activated factor-1 (Apaf-1) and caspase-9, and activation of caspases. These data suggest that SS-31 may prevent podocyte apoptosis, exerting renal protection in diabetes mellitus, probably through an apoptosis-related signalling pathway involving oxidative stress and culminating in mitochondria.

The Role of PGC-1α and Mitochondrial Biogenesis in Kidney Diseases

“…SS peptides promote ATP synthesis, reduce electron leak and ROS production, and inhibit cardiolipin peroxidation [134], preventing the consequences of mitochondrial dysfunction, including apoptosis, inflammation, and NLRP3 inflammasome activation [134]. Specifically, SSP3 protected from experimental AKI [135] and in kidney injury in T1DM induced by streptozotocin in rats [136]. MitoQ, MitoTEMPO, or SkQR1 also reduced oxidative damage and renal inflammation [134,[137][138][139].…”

Self-assembly of mitochondria-specific peptide amphiphiles amplifying lung cancer cell death through targeting the VDAC1–hexokinase-II complex

“…[1][2][3] They currently underlie new drug developments, which will complement the existing therapies for cancer cells killing and cancer elimination. [4][5][6][7][8][9][10][11][12] The mitochondrial-targeting anti-cancer mechanisms include the activation of mitochondria-mediated apoptotic pathways via voltagedependent-anion-channel (VDAC) targeting agents or electron transport/respiratory chain blockers, [13][14][15] the increased induction of reactive oxygen species (ROS), 16,17 the inhibition of the Bcl-2 anti-apoptotic family of proteins, 18 the activation of the mitochondrial membrane permeability transition pore protein subunits, 19,20 the mtDNA targeting in cancer cells, 19 and treatments involving mitochondrial destabilization, mitochondrial membrane permeabilization, 21 mitochondrial fission and massive mitochondrial fragmentation using lipophilic cations targeting the inner membrane. [22][23][24][25][26][27][28] Hexokinase-II (HK-II) is increasingly regarded as an attractive therapeutic target for cancer therapy based on its key role in glycolysis as a part of the cell energy metabolism.…”

Mitochondria-Targeted Peptide SS31 Attenuates Renal Tubulointerstitial Injury via Inhibiting Mitochondrial Fission in Diabetic Mice

“…SS31 peptide (H-D-Arg-Dmt-Lys-Phe-NH2) could specially concentrate in the inner mitochondrial membrane. It has been demonstrated that SS31 has excellent therapeutic efficacy in myocardial injury, neurodegeneration injury, and diabetic complications [7–10]. Our previous study demonstrated that mitochondria-targeted peptides (MTP131 and SPI20) could prevent contrast-induced acute kidney injury in rats [11].…”