Gamma-interferon-inducible lysosomal thiol reductase maintains cardiac immuno-metabolic homeostasis in heart failure

Heart failure (HF) remains the leading cause of death globally. The progression of HF is characterized by cardiac mitochondrial dysfunction and aberrant inflammatory responses. Although the lysosome has been recognized as the central player for maintaining immuno-metabolic homeostasis in diverse organs in health and disease, the mechanistic insights into the regulation of lysosome-dependent immuno-metabolism in the heart are lacking. Lysosomal reductase Gamma Interferon-Inducible Thiol Reductase (GILT) is the only identified lysosomal reductase that controls more than 11 lysosomal enzymes, and a single nucleotide polymorphism in the coding sequence of GILT has been implicated in promoting cardiovascular risk. Here, we show that GILT expression and activity are reduced in hearts from human patients and mice with HF, respectively. Moreover, cardiomyocyte-specific deletion of GILT (GILT-cKO) results in left ventricular remodeling and dysfunction in the setting of pressure overload. At the cellular level, cardiac GILT deficiency leads to impaired mitochondrial respiration, elevated mitochondrial oxidative stress, and increased NLR Family Pyrin Domain Containing 3(NLRP3)-dependent inflammation in the heart. Mechanistically, inhibition of NLRP3 in primary cardiomyocytes ameliorated the mitochondrial dysfunction in the GILT deficient cells, implicating a causative role of the lysosome-inflammasome axis on regulating cardiac mitochondrial function. Together, these findings elucidate a functional link between cardiac lysosomes, inflammatory responses and mitochondrial respiration. Knowledge gained from this study might speed the development of therapeutic agents to treat patients with HF.