We showed that SIRT3 deficiency exacerbated Ang II–induced downregulation of the efferocytosis receptor MerTK (c-Mer tyrosine kinase) and proinflammatory cytokine production, accompanied by disrupted mitochondrial iron homeostasis in cardiac macrophages. Quantitative acetylome analysis revealed that SIRT3 deacetylated FXN (frataxin) at lysine 189. Ang II attenuated SIRT3 activity and enhanced the acetylation level of FXN K189. Acetylated FXN further reduced the synthesis of ISCs (iron-sulfur clusters), resulting in mitochondrial iron accumulation. Phagocytic internalization of apoptotic cardiomyocytes increased myoglobin content, and derived iron ions promoted mitochondrial iron overload and lipid peroxidation. An iron chelator deferoxamine improved the levels of MerTK and efferocytosis, thereby attenuating proinflammatory macrophage activation. FXNK189R mice showed improved macrophage efferocytosis, reduced cardiac inflammation, and suppressed cardiac fibrosis.
Thursday, August 31, 2023
SIRT3 Regulates Clearance of Apoptotic Cardiomyocytes by Deacetylating Frataxin
Jing Gao, Chenglin Huang, Linghui Kong, Wugang Zhou, Mengwei Sun, Tong Wei and Weili Shen. Circulation Research. 2023;0. Originally published 30 Aug 2023 doi:10.1161/CIRCRESAHA.123.323160
Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo
Maria M. Krasilnikova & Sergei M. Mirkin (2004) Replication Stalling at Friedreich's Ataxia (GAA)n Repeats In Vivo, Molecular and Cellular Biology, 24:6, 2286-2295, DOI: 10.1128/MCB.24.6.2286-2295.2004
We believe that repeat-caused replication attenuation in vivo is due to triplex formation. The apparent link between the replication stalling and length polymorphism of the repeat points to a new model for the repeat expansion.
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