Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin

Abstract

Organic acidemias such as methylmalonic acidemia (MMA) are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino and fatty acids. Accretion of acyl-CoA species is postulated to underlie disease pathophysiology, but the mechanism(s) remain unknown. Here, we surveyed hepatic explants from patients with MMA and unaffected donors, in parallel with samples from various mouse models of methylmalonyl-CoA mutase deficiency. We found a widespread posttranslational modification, methylmalonylation, that inhibited enzymes in the urea cycle and glycine cleavage pathway in MMA. Biochemical studies and mouse genetics established that sirtuin 5 (SIRT5) controlled the metabolism of MMA-related posttranslational modifications. SIRT5 was engineered to resist acylation-driven inhibition via lysine to arginine mutagenesis. The modified SIRT5 was used to create an adeno-associated viral 8 (AAV8) vector and systemically delivered to mutant and control mice. Gene therapy ameliorated hyperammonemia and reduced global methylmalonylation in the MMA mice.

Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia

“…The rate of CoASH biosynthesis is also governed in tissues by the expression levels of the three PANK isoforms, leading to the observed variations in tissue CoA concentrations. 71 Correcting liver metabolism with liver transplantation 26 , 27 , 28 , 29 , 30 , 31 , 32 or gene or RNA 33 , 34 , 35 , 36 , 37 therapy to restore liver PCC activity will not directly alter the extent of cellular CoASH sequestration or mitochondrial dysfunction in the other body tissues because CoA formation and mitochondrial metabolism are cell autonomous. PA patients have impaired neurocognitive development, 72 and as a small molecule that penetrates the brain, BBP‐671 has the potential to correct CoASH sequestration and defective TCA cycles in the brain and other affected tissues.…”

“…Human liver transplantation can lower the circulating concentrations of PA biomarkers and improve the quality of life, though transplant patients remain at risk of developing complications 26–32 . Gene or RNA therapies under active development reduce the concentrations of PA biomarkers in mouse models 33–37 . Small molecule therapeutic strategies are also under exploration 38,39 .…”

“… 26 , 27 , 28 , 29 , 30 , 31 , 32 Gene or RNA therapies under active development reduce the concentrations of PA biomarkers in mouse models. 33 , 34 , 35 , 36 , 37 Small molecule therapeutic strategies are also under exploration. 38 , 39 PANK activity is potently inhibited by C3‐CoA and this inhibition is reversed by PZ‐3022, a representative member of a drug‐like series of allosteric PANK activators, called pantazines, that elevate tissue CoA, 40 , 41 attenuate the inhibition of PANK activity by C3‐CoA and improve mitochondrial function in a PA mouse model.…”

New Histone Lysine Acylation Biomarkers and Their Roles in Epigenetic Regulation

“…For instance, SIRT5 targets negatively charged lysine acylations especially succinylation and malonylation (Peng et al, 2011;, and SIRT6 preferentially removes long-chain fatty acyl marks over acetylation from the lysine side chain (Feldman et al, 2013). The sirtuin orthologs as KDACs are found in both eukaryotes and prokaryotes (the same conservation is seen for the GNAT family members as KATs) (Marsh (Head et al, 2022(Head et al, ) et al, 2005Starai & Escalante-Semerena, 2004;Vetting et al, 2005;K. Zhao et al, 2004).…”

“…In addition to lysine acetylation, ∼20 different types of lysine acylations have been discovered (Table 1), which include myristylation (C14) (Bursten et al., 1988), formylation (Kfo) (T. Jiang et al., 2007), propionylation (Kpr), butyrylation (Kbu) (Chen et al., 2007), crotonylation (Kcr) (M. Tan et al., 2011), succinylation (Ksucc), malonylation (Kmal) (Z. Y. Xie et al., 2012), methylmalonylation (Kmma) (Head et al., 2022), glutarylation (Kglu) (M. Tan et al., 2014), 2‐hydroxyisobutyrylation (Khib) (Dai et al., 2014), β‐hydroxybutyrylation (Kbhb) (Z. Xie et al., 2016), 3‐hydroxy‐3‐methylglutarylation (K HMG ), 3‐methylglutaconylation (K MGc ), 3‐methylglutarylation (K MG ) (Wagner et al., 2017), benzoylation (Kbz) (Huang et al., 2018), lactylation (Kla) (D. Zhang, et al., 2019), isonicotinylation (Kinic) (Y. Jiang et al., 2021), methacrylation (Kmea) (Delaney et al., 2021), and isobutyrylation (Kibu) (Zhu et al., 2021). Abundances of different acylation marks are reliant on the cellular concentrations of corresponding acyl‐CoA metabolites, strongly demonstrating the intimate coupling of epigenetic regulation with cellular metabolism (Sabari et al., 2017; Simithy et al., 2017; M. Wang & Lin, 2021).…”