Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome

Shen Li; Hongbo Liu; Hailong Hu; Eunji Ha; Praveena Prasad; Brenita C Jenkins; Ujjalkumar Subhash Das; Sarmistha Mukherjee; Kyosuke Shishikura; Renming Hu; Daniel J Rader; Liming Pei; Joseph A Baur; Megan L Matthews; Garret A FitzGerald; Melanie R McReynolds; Katalin Susztak

doi:10.1016/j.cmet.2024.10.007

Human genetics identify convergent signals in mitochondrial LACTB-mediated lipid metabolism in cardiovascular-kidney-metabolic syndrome

Cell Metab. 2024 Nov 14:S1550-4131(24)00403-0. doi: 10.1016/j.cmet.2024.10.007. Online ahead of print.

Authors

Shen Li¹, Hongbo Liu¹, Hailong Hu¹, Eunji Ha¹, Praveena Prasad², Brenita C Jenkins², Ujjalkumar Subhash Das³, Sarmistha Mukherjee⁴, Kyosuke Shishikura⁵, Renming Hu⁵, Daniel J Rader⁶, Liming Pei⁷, Joseph A Baur⁸, Megan L Matthews⁵, Garret A FitzGerald³, Melanie R McReynolds², Katalin Susztak⁹

Affiliations

¹ Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Penn/CHOP Kidney Innovation Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
³ Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁴ Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Division of Translational Medicine and Human Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Center for Mitochondrial and Epigenomic Medicine, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁹ Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Penn/CHOP Kidney Innovation Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: ksusztak@pennmedicine.upenn.edu.

PMID: 39561766
DOI: 10.1016/j.cmet.2024.10.007

Abstract

The understanding of cardiovascular-kidney-metabolic syndrome remains difficult despite recently performed large scale genome-wide association studies. Here, we identified beta-lactamase (LACTB), a novel gene whose expression is targeted by genetic variations causing kidney dysfunction and hyperlipidemia. Mice with LACTB deletion developed impaired glucose tolerance, elevated lipid levels, and increased sensitivity to kidney disease, while mice with tubule-specific overexpression of LACTB were protected from kidney injury. We show that LACTB is a novel mitochondrial protease cleaving and activating phospholipase A2 group VI (PLA2G6), a kidney-metabolic risk gene itself. Genetic deletion of PLA2G6 in tubule-specific LACTB-overexpressing mice abolished the protective function of LACTB. Via mouse and human lipidomic studies, we show that LACTB and downstream PLA2G6 convert oxidized phosphatidylethanolamine to lyso-phosphatidylethanolamine and thereby regulate mitochondrial function and ferroptosis. In summary, we identify a novel gene and a core targetable pathway for kidney-metabolic disorders.

Keywords: GWAS; cardiovascular-kidney-metabolic syndrome; ferroptosis; genetics; kidney disease; mitochondria; phospholipase; phospholipid; serine protease.