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. 2022 Nov 18;12(1):19847.
doi: 10.1038/s41598-022-24231-4.

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

Silvia Russo #  1 , Domenico De Rasmo #  2 , Anna Signorile  1 , Angela Corcelli  1 , Simona Lobasso  3
Affiliations

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

Silvia Russo et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Negative ion mode MALDI-TOF/MS lipid profiles of TazKD (red) and WT (blue) cardiac mitochondria. Mitochondria were isolated from 4-month-old mice and representative lipid mass spectra are shown in (A). Lipid assignments for main signals are indicated. The enlargement of the range m/z 1100 to 1500 of the mass spectrum of TazKD is also shown. The histograms in (B) show the significant differences in intensity between the lipid peaks in the two series of (−) MALDI mass spectra. Data are reported as the average value of intensity ± SD. A p-value < 0.05 was set as the threshold for significant differences between the two series of mass spectra (*p < 0.05; **p < 0.01; ***p < 0.001). The numbers under each histogram indicate the detected MALDI m/z peaks.
Figure 2
Figure 2
Positive ion mode MALDI-TOF/MS total lipid profiles of TazKD (red) and WT (blue) cardiac mitochondria (A). Mitochondria were isolated from 4-month-old mice and representative lipid mass spectra are shown in (A). Lipid assignments for main signals are indicated. The histograms (B) show the significant differences in intensity between the lipid peaks in the two series of (+) mass spectra. Data are reported as the average value of intensity ± SD. A p-value < 0.05 was set as the threshold for significant differences between the series of mass spectra (*p < 0.05; **p < 0.01; ***p < 0.001, ****p < 0.0001). The numbers under each histogram indicate the detected MALDI m/z peaks.
Figure 3
Figure 3
(MLCL + CLi)/CLm ratios calculated by MALDI-TOF/MS analysis of mitochondria. Mitochondrial lipids were analysed by (−) MALDI analysis (in triplicate for each sample) and ratios were calculated as described in “Methods”. The scatter plot shows the measurements of all mitochondrial samples for each group of mice (8 WT, 8 TazKD, 4 TazKD + saline, and 4 TazKD + SS-31) and the average values with the error bars indicating SD (****p < 0.0001). The y-axis shows a logarithmic scale.
Figure 4
Figure 4
Cardiac mitochondria respiratory rates and effect of SS-31. The oxygen consumption rate of non-phosphorylating (state 4) (A) and phosphorylating (state 3) (B) with succinate as respiratory substrate. Full uncoupling of the succinate-dependent respiration rate was assessed in the presence of 0.25 μM CCCP (C). The respiratory control ratio (RCR) was calculated by the state 3/post-oligomycin respiration ratio (D). Histograms display the mean values ± SD (n = 4/group). Statistically significant differences are indicated: Student’s t-test (**p < 0.01, *p < 0.05).
Figure 5
Figure 5
Respiratory chain supercomplex organization analysis. Isolated cardiac mitochondria were separated by BN-PAGE, transferred onto PVDF membrane, and subjected to western blotting analysis with specific antibodies, as indicated. Supercomplexes (SC4, SC3, SC2, and SC1) containing complex I and complex III in various amounts are shown. Complex I (Cx I) and complex III (Cx III) are also identified as monomers (A, D). Protein levels estimated by band densitometry (B, C, E, F) in TazKD and TazKD + SS-31 are expressed as percentages vs WT and TazKD + saline, respectively. Histograms G and H display the percentage of ADU of immune-revealed bands in free complexes and in supercomplexes in each lane. All histograms show the mean values ± SD (n = 4/group). Statistically significant differences are indicated: Student’s t-test (**p < 0.01, *p < 0.05).
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