Figure 10. mtISR leads to mitochondrial dysfunction and systemic metabolic remodeling in CHCHD10S55L mice.
A. Western blots of total heart homogenates for MTHFD1L, MTHFD2, ATF4, p62, phospho-S6, total S6. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is used as a loading control. B. Cardiomyocyte immunolabeling for p62 (green) and Tom20 (red). The right panels show the merged images. Bars = 20 μm. C. Average oxygen consumption rates in freshly isolated heart mitochondria measured with complex I (glutamate/malate) and complex II (glutamate/succinate) substrates and expressed as a percentage of WT. n=6. Error bars indicate SEM. **p<0.01 by Students t-test. D. Average FGF-21 levels in mouse serum at 180 days (n = 10 WT, 6 CHCHD10S55L, 4 KO), 280 days (n = 2 WT, 6 CHCHD10S55L, 2 KO), and 380 days (n = 8 WT, 4 CHCHD10S55L, 2 KO) expressed relative to WT. Error bars indicate SEM. ***p<0.001 by Student’s t-test. E. Visceral (top panel) and subcutaneous (lower panel) fat pads at necropsy. F. Schematic representation of the pathway of mTORC1/ATF4-mediated mtISR triggered by CHCHD10/2 aggregation and mitochondrial dysfunction in CHCHD10S55L mice.