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

Abstract

Objective. Renal tubular injury is an early characteristic of diabetic nephropathy (DN) that is related to mitochondrial dysfunction. In this study, we explore the effects and mechanisms of mitochondria-targeted peptide SS31 on renal tubulointerstitial injury in DN. Method. 40 C57BL/6 mice were randomly divided into control group, STZ group, STZ+SS31 group, and STZ+normal saline group. SS31 was intraperitoneally injected to the mice every other day for 24 weeks. Renal lesions and the expression of Drp1, Mfn1, Bcl-2, Bax, Caspase1, IL-1β, and FN were detected. In in vitro studies, HK-2 cells were incubated with different concentrations of D-glucose (5, 30 mM) or combined with SS31 and Drp1 inhibitor Midivi1. Mitochondrial ROS, membrane potential, and morphology have been detected to evaluate the mitochondrial function. Results. Compared with diabetic mice, the levels of serum creatinine and microalbuminuria were significantly decreased in the SS31 group. Renal tubulointerstitial fibrosis, oxidative stress, and apoptosis were observed in diabetic mice, while the pathological changes were reduced in the SS31-treatment group. SS31 could decrease the expression of Drp1, Bax, Caspase1, IL-1β, and FN in the renal tissue of diabetic mice, while increasing the expression of Mfn1. Additionally, mitochondria exhibit focal enlargement and crista swelling in renal tubular cells of diabetic mice, while SS31 treatment could partially block these changes. An in vitro study showed that pretreatment with SS31 or Drp1 inhibitor Mdivi1 could restore the level of mitochondrial ROS, the membrane potential levels, and the expressions of Drp1, Bax, Caspase1, IL-1β, and FN in HK-2 cells under high-glucose conditions. Conclusion. SS31 protected renal tubulointerstitial injury in diabetic mice through a decrease in mitochondrial fragmentation via suppressing the expression of Drp1 and increasing the expression of Mfn1.

The Effects of a Mitochondrial Targeted Peptide (Elamipretide/SS31) on BAX Recruitment and Activation During Apoptosis

“…A variety of factors could account for the bene cial effects of elamipretide including stabilization of mitochondrial cristae structure [22], modulation of lipid surface properties including charge [28], and improved mitochondrial function and transport [27]. Some reports suggest that elamipretide also impairs the recruitment of BAX to the mitochondria [24] and prevents mitochondrial ssion [21] during apoptosis, which is consistent with a role in attenuating cell death. Given the ability of elamipretide to associate with cardiolipins and to stabilize cristae structure [22], we hypothesized that elamipretide may alter BAX recruitment to the MOM and/or inhibit downstream events associated with BAX activation such as MOMP and mitochondrial fragmentation.…”

“…The mitochondrial-targeted peptide elamipretide (SS31) has consistently been shown to ameliorate agerelated conditions affecting muscle, cardiac, ocular, and nephrotic tissues [18][19][20][21][22] and has been shown to be protective in animal models of neurodegeneration [23][24][25][26][27]. A variety of factors could account for the bene cial effects of elamipretide including stabilization of mitochondrial cristae structure [22], modulation of lipid surface properties including charge [28], and improved mitochondrial function and transport [27].…”

Quercetin Antagonizes Glucose Fluctuation Induced Renal Injury by Inhibiting Aerobic Glycolysis via HIF-1α/miR-210/ISCU/FeS Pathway

“…Our finding provided the evidence that swing of glucose also induced abnormal expression of miR-210 in a mouse glomerular MCs cell line. Considering HIF-1α/miR-210 are involving in GF ( 11 ), DN ( 12 ), and Warburg effect ( 13 ), it is reasonable to believe that this axis may be a vital target in the treatment of GF-related damage and the prevention of DN. ISCU/FeS pathway is the down-stream target of HIF-1α/miR-210.…”

“…Disturbance of FeS assembly contributes to the development of DN via inactivation of FeS-dependent enzymes, such as complex I ( 10 ). HIF-1α is also considered to play roles among GF ( 11 ), DN ( 12 ), and Warburg effect ( 13 ). Mitochondria are the major sites for regulating glucose metabolism of cells.…”

“…Mitochondria are the major sites for regulating glucose metabolism of cells. In the condition of glucose intermittent, hypoxia-inducible factor 1α (HIF-1α) enhances its transcriptional activity triggered by dysfunction of mitochondria ( 11 ). Thus, it is meaningful to investigate whether HIF-1α/miR210/ISCU/FeS axis underlies aerobic glycolysis in conditions of GF induced renal injury.…”