bims-meprid 2025-01-05 papers

Nat Commun. 2025 Jan 02. 16(1): 345

Pantothenate kinase 4 controls skeletal muscle substrate metabolism.

Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl-CoA levels. Elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism.

DOI: https://doi.org/10.1038/s41467-024-55036-w

Adv Sci (Weinh). 2024 Dec 31. e2411943

Aldehyde Dehydrogenase 2 Lactylation Aggravates Mitochondrial Dysfunction by Disrupting PHB2 Mediated Mitophagy in Acute Kidney Injury.

Jiaying Li, Xiaoxiao Shi, Jiatong Xu, Kaiyue Wang, Fangxing Hou, Xiaodong Luan, Limeng Chen.

Mitochondrial dysfunction is a crucial event in acute kidney injury (AKI), leading to a metabolic shift toward glycolysis and increased lactate production. Lactylation, a posttranslational modification derived from lactate, plays a significant role in various cellular processes, yet its implications in AKI remain underexplored. Here, a marked increase in lactate levels and pan-Kla levels are observed in kidney tissue from AKI patients and mice, with pronounced lactylation activity in injured proximal tubular cells identified by single-cell RNA sequencing. The lactylation of aldehyde dehydrogenase 2 (ALDH2) is identified at lysine 52 (K52la), revealing that ALDH2 lactylation exacerbates tubular injury and mitochondrial dysfunction. Conversely, the ALDH2 K52R mutation alleviates these injuries in HK-2 cells and adeno-associated virus-infected kidney tissues in mice. Furthermore, ALDH2 lactylation can be modulated by upregulating SIRT3 in vivo and in vitro, which reduces ALDH2 lactylation, mitigating tubular injury and mitochondrial dysfunction. Mechanistically, immunoprecipitation-mass spectrometry analysis demonstrates an interaction between ALDH2 and prohibitin 2 (PHB2), a crucial mitophagy receptor. ALDH2 lactylation promotes the ubiquitination-proteasomal degradation of PHB2 to inhibit mitophagy and worsen mitochondrial dysfunction. These findings highlight the critical role of endogenous lactate in AKI and propose ALDH2 lactylation as a potential therapeutic target.

Keywords: ALHD2; acute kidney injury; lactylation; mitochondrial function; mitophagy

DOI: https://doi.org/10.1002/advs.202411943

J Exp Med. 2025 Feb 03. pii: e20240625. [Epub ahead of print]222(2):

The phospholipid kinase PIKFYVE is essential for Th17 differentiation.

Douglas S Prado, Richard T Cattley, Andreza B Sonego, Parth Sutariya, Shuxian Wu, Mijoon Lee, William C Boggess, Mark J Shlomchik, William F Hawse.

T helper 17 (Th17) cells are effector cells that mediate inflammatory responses to bacterial and fungal pathogens. While the cytokine signaling inputs required to generate Th17s are established, less is known about intracellular pathways that drive Th17 differentiation. Our previously published phosphoproteomic screen identifies that PIKFYVE, a lipid kinase that generates the phosphatidylinositol PtdIns(3,5)P2, is activated during Th17 differentiation. Herein, we discovered that PIKFYVE regulates kinase and transcription factor networks to promote Th17 differentiation. As a specific example, PtdIns(3,5)P2 directly stimulates mTORC1 kinase activity to promote cell division and differentiation pathways. Furthermore, PIKFYVE promotes STAT3 phosphorylation, which is required for Th17 differentiation. Chemical inhibition or CD4-specific deletion of PIKFYVE reduces Th17 differentiation and autoimmune pathology in the experimental autoimmune encephalomyelitis murine model of multiple sclerosis. Our findings identify molecular mechanisms by which PIKFYVE promotes Th17 differentiation and suggest that PIKFYVE is a potential therapeutic target in Th17-driven autoimmune diseases.

DOI: https://doi.org/10.1084/jem.20240625

BMC Cardiovasc Disord. 2024 Dec 30. 24(1): 757

OGT-mediated O-GlcNAcylation regulates macrophage polarization in heart failure via targeting IRF1.

Guoqiang Jing, Yuhong Ma.

BACKGROUND: Heart failure (HF) is a syndrome with complex etiology and high mortality in the world. Macrophage-related inflammation is involved in HF development. O-GlcNAcylation is a post-translational modification that affects pathological processes. This study aimed to investigate the role of O-GlcNAcylation in HF, especially its effect on macrophage polarization.
METHODS: Raw264.7 cells were treated with lipopolysaccharide (LPS) to induce pro-inflammatory macrophages. HF mice were generated by transverse aortic constriction (TAC). After knockdown of OGT or overexpressing IRF1, macrophage polarization was evaluated using quantitative real-time polymerase chain reaction and flow cytometry. Underlying mechanism was analyzed using bioinformatic analysis, co-immunoprecipitation (co-IP), IP, and western blotting.
RESULTS: The results showed that O-GlcNAcylation and OGT levels were high in LPS-treated Raw264.7 cells. OGT knockdown inhibited pro-inflammatory macrophage polarization and promoted anti-inflammatory macrophage polarization caused by LPS, and alleviated TAC-induced cardiac dysfunction and fibrosis. Mechanistically, OGT silence suppressed O-GlcNAcylation of IRF1 at Ser (S)283 site. IRF1 overexpression reversed macrophage polarization modulated by OGT knockdown.
CONCLUSION: Silencing of OGT promotes macrophage polarization from pro-inflammatory to anti-inflammatory phenotype to alleviate HF through O-GlcNAcylation of IRF1. The findings suggest that O-GlcNAcylation has the potential to treat HF.

Keywords: Heart failure; IRF2; Lipopolysaccharide; O-GlcNAcylation; OGT; Pro-/anti-inflammatory macrophage

DOI: https://doi.org/10.1186/s12872-024-04429-2