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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 <jats:italic>TAFAZZIN<\/jats:italic> knockdown (Taz<jats:sup>KD<\/jats:sup>) 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 Taz<jats:sup>KD<\/jats:sup> cardiac mitochondria obtained by MALDI-TOF\/MS revealed the typical lipid changes associated with BTHS. Taz<jats:sup>KD<\/jats:sup> mitochondria showed lower respiratory rates in state 3 and 4 together with a decreased in maximal respiratory rates. Treatment of Taz<jats:sup>KD<\/jats:sup> 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.<\/jats:p>","DOI":"10.1038\/s41598-022-24231-4","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T15:04:10Z","timestamp":1668783850000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Beneficial effects of SS-31 peptide on cardiac mitochondrial dysfunction in tafazzin knockdown mice"],"prefix":"10.1038","volume":"12","author":[{"given":"Silvia","family":"Russo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"De Rasmo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Signorile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Corcelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3566-4547","authenticated-orcid":false,"given":"Simona","family":"Lobasso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,11,18]]},"reference":[{"key":"24231_CR1","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/0022-510X(83)90209-5","volume":"62","author":"PG Barth","year":"1983","unstructured":"Barth, P. 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