PDHA1 hyperacetylation-mediated lactate overproduction promotes sepsis-induced acute kidney injury via Fis1 lactylation

Abstract

The increase of lactate is an independent risk factor for patients with sepsis-induced acute kidney injury (SAKI). However, whether elevated lactate directly promotes SAKI and its mechanism remain unclear. Here we revealed that downregulation of the deacetylase Sirtuin 3 (SIRT3) mediated the hyperacetylation and inactivation of pyruvate dehydrogenase E1 component subunit alpha (PDHA1), resulting in lactate overproduction in renal tubular epithelial cells. We then found that the incidence of SAKI and renal replacement therapy (RRT) in septic patients with blood lactate ≥ 4 mmol/L was increased significantly, compared with those in septic patients with blood lactate < 2 mmol/L. Further in vitro and in vivo experiments showed that additional lactate administration could directly promote SAKI. Mechanistically, lactate mediated the lactylation of mitochondrial fission 1 protein (Fis1) lysine 20 (Fis1 K20la). The increase in Fis1 K20la promoted excessive mitochondrial fission and subsequently induced ATP depletion, mitochondrial reactive oxygen species (mtROS) overproduction, and mitochondrial apoptosis. In contrast, PDHA1 activation with sodium dichloroacetate (DCA) or SIRT3 overexpression decreased lactate levels and Fis1 K20la, thereby alleviating SAKI. In conclusion, our results show that PDHA1 hyperacetylation and inactivation enhance lactate overproduction, which mediates Fis1 lactylation and exacerbates SAKI. Reducing lactate levels and Fis1 lactylation attenuate SAKI.

Tubule-specific cyclin-dependent kinase 12 knockdown potentiates kidney injury through transcriptional elongation defects

“… 38 Previous studies have shown that cell cycle arrest and acetylation and lactylation modifications occur after injury in several models of AKI. 39 , 40 Clearly, these data showed that CDK12 knockdown in tubular cells could induce cellular injury through DNA damage and subsequently cause apoptosis and inhibition of proliferation.…”

An early warning model for predicting major adverse kidney events within 30 days in sepsis patients

“…Furthermore, lactate is also implicated in lactylation processes ( 25 ). An et al discovered that hyperacetylation and subsequent inactivation of the pyruvate dehydrogenase E1 component subunit alpha (PDHA1) lead to an increase in lactate production, which in turn promotes the lactylation of the mitochondrial fission 1 protein (Fis1) and worsens the severity of S-AKI ( 28 ). Conversely, decreasing lactate levels and Fis1 lactylation can alleviate S-AKI ( 28 ).…”

“…An et al discovered that hyperacetylation and subsequent inactivation of the pyruvate dehydrogenase E1 component subunit alpha (PDHA1) lead to an increase in lactate production, which in turn promotes the lactylation of the mitochondrial fission 1 protein (Fis1) and worsens the severity of S-AKI ( 28 ). Conversely, decreasing lactate levels and Fis1 lactylation can alleviate S-AKI ( 28 ). Additionally, our findings revealed a significant association between lactate and MAKE30 in sepsis patients, underscoring the importance of therapeutic interventions aimed at reducing blood lactate levels in septic patients.…”

Uncovering impaired mitochondrial and lysosomal function in adipose-derived stem cells from obese individuals with altered biological activity

“…We also observed the mitochondrial homeostasis or dynamics was disrupted, as indicated by decreased mitochondrial membrane fluidity, the broken balance of fusion/fission, increased mitochondrial fragmentation in O-ADSCs. Previous study showed that excess mitochondrial fission may promote mitochondrial dysfunctions and lead to cell injury [ 53 , 54 ]. The data reveal that impaired mitochondrial morphology and structure lead to mitochondrial dysfunction, which leads to cell injury in O-ADSCs and ultimately to the reduction of cell activity.…”