Caffeine and SS-31 are Potential Treatments for Bardet-Biedl Syndrome via Improvement of Mitochondrial Function

Younes Rouabhi; Deng Fu Guo; Kamal Rahmouni

doi:10.1152/physiol.2025.40.S1.0655

Abstract only Bardet-Biedl Syndrome (BBS) is a genetic condition that is characterized by multiple features including obesity and type 2 diabetes. Recently, our group showed that disruption of the BBSome, a protein complex of eight BBS proteins, is associated with mitochondrial defects due to a decrease in the activity of key mitochondrial fission protein, dynamin-related protein 1 (DRP1). Prior reports have demonstrated that caffeine promotes mitochondrial fission, resulting in shortening of the mitochondria and a subsequent improvement in mitochondria quality. Interestingly, this was associated with improvement in obesity and insulin resistance. Similarly, Elamipretide (SS-31) is a synthetic peptide that has been primarily used to target a variety of mitochondrial disorders. Because of their shown involvement in maintaining healthy mitochondria quality, we hypothesized that caffeine and SS-31 treatments will lead to improved mitochondrial function in BBS cells by increasing the activity of DRP1. Subsequently, we postulated that caffeine and SS-31 treatment will improve body weight and glucose homeostasis in BBS mice. To test our hypothesis, mouse hypothalamic N39 cells lacking the Bbs1 gene (Bbs1KO) were treated with 50 μM caffeine, 50 nM SS-31, or vehicle. Cell morphology was assessed via transmission electron microscopy. We found that treatment of Bbs1KO cells with both caffeine and SS-31 improved mitochondria dynamics as indicated by the decrease in mitochondria length, area, and form factor (length untreated: 1.31±0.07 vs caffeine: 1.13±0.04 and SS-31: 0.95±0.04 μm, p<0.05). Furthermore, proteins from these cells were extracted and processed via Western blot to assess levels of DRP1 phosphorylation. Mitochondrial reactive oxygen species in Bbs1KO cells were also quantified using Mito-SOX fluorescence indicator. Bbs1KO cells treated with caffeine and SS-31 showed heightened levels of phosphorylated DRP1 (untreated: 1±0.16 vs caffeine: 1.65±0.22 and SS-31: 2.54±0.34 AU, p<0.05) and reduced reactive oxygen species (untreated: 9845±770 vs caffeine: 4841±292 and SS-31: 6242±400 CTCF, p<0.05) compared to untreated cells. Next, mice lacking the Bbs1 gene were treated with 50 mg/kg caffeine BID for 6 weeks beginning at 8 weeks of age. Body weight, weekly food intake, glucose handling (measured via glucose tolerance test, GTT) and insulin sensitivity (measured via insulin tolerance test, ITT) were compared to wildtype littermate controls. Preliminary data show that caffeine treatment trended to attenuate weight gain and improve glucose handling in BBS1 global knockout mice. Additional studies are underway to complete these results. Ultimately, these findings suggest caffeine and SS-31 as potential effective therapies to mitigate the obesity and diabetes associated with BBS. NIH NHLBI T35HL166206 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Caffeine and SS-31 are Potential Treatments for Bardet-Biedl Syndrome via Improvement of Mitochondrial Function

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