Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in tafazzin knockdown mice.

Abstract

Barth Syndrome (BTHS), a genetic disease associated with early-onset cardioskeletal myopathy, is caused by loss-of-function mutations of the TAFAZZIN gene, which is responsible for remodeling the mitochondrial phospholipid cardiolipin (CL). Deregulation of CL biosynthesis and maturation in BTHS mitochondria result in a dramatically increased monolysocardiolipin (MLCL)/CL ratio associated with bioenergetic dysfunction. One of the most promising therapeutic approaches for BTHS includes the mitochondria-targeted tetrapeptide SS-31, which interacts with CL. Here, we used TAFAZZIN knockdown (TazKD) mice to investigate for the first time whether in vivo administration of SS-31 could affect phospholipid profiles and mitochondrial dysfunction. The CL fingerprinting of TazKD cardiac mitochondria obtained by MALDI-TOF/MS revealed the typical lipid changes associated with BTHS. TazKD mitochondria showed lower respiratory rates in state 3 and 4 together with a decreased in maximal respiratory rates. Treatment of TazKD mice with SS-31 improved mitochondrial respiratory capacity and promoted supercomplex organization, without affecting the MLCL/CL ratio. We hypothesize that SS-31 exerts its effect by influencing the function of the respiratory chain rather than affecting CL directly. In conclusion, our results indicate that SS-31 have beneficial effects on improving cardiac mitochondrial dysfunction in a BTHS animal model, suggesting the peptide as future pharmacologic agent for therapy.

• Authors: Silvia Russo, Domenico De Rasmo, Anna Signorile, Angela Corcelli, Simona Lobasso
• Journal: Scientific reports (Sci Rep) Vol. 12 Issue 1 Pg. 19847 (11 18 2022) ISSN: 2045-2322 [Electronic] England
• PMID: 36400945 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
• Acyltransferases
• Transcription Factors
• Cardiolipins
• Phospholipids

Topics

• Mice
• Animals
• Acyltransferases (genetics)
• Transcription Factors (genetics)
• Barth Syndrome (genetics)
• Cardiolipins
• Mitochondria, Heart
• Phospholipids