Mitochondrial regulation of lactylation in sepsis-induced cardiomyopathy

Fig. 1. Panel A illustrates the mechanisms of midzone and peripheral fission. Panel B depicts the fate of daughter mitochondria resulting from each fission type. Red arrows denote pathways associated with peripheral fission (<25% from the tip), and black arrows indicate midzone fission (central 50% region). Dynamin-related protein 1 (Drp1) coordinates both types of fission. Midzone fission (Panel A, left): The endoplasmic reticulum (ER) anchors to mitochondria via PDZD8 contact sites. Inverted formin 2 (INF2)-dependent actin polymerization drives preconstriction. Mitochondrial fission factor (MFF) forms high-intensity clusters (2× brighter than the periphery) that recruit Drp1. Peripheral fission (Panel A, right): Lysosomes dock via TBC1D15 at mitochondrial tips. The mitochondrial fission 1 protein (Fis1) is enriched at damage sites to recruit Drp1 and Parkin. Fate of daughter mitochondria (Panel B): Midzone fission generates functional mitochondria with intact mitochondrial DNA (mtDNA) and membrane potential (ΔΨm), supporting biogenesis. Peripheral fission produces small fragments that sequester damaged components with low ΔΨm and increased reactive oxygen species/calcium (ROS/Ca²⁺)…

Fig. 2. Metabolic reprogramming and increased lactate-mediated lactylation in sepsis-induced cardiomyopathy. This schematic illustrates the key metabolic alterations driving mitochondrial dysfunction in SICM. Sepsis triggers a shift from mitochondrial oxidative phosphorylation to glycolysis, resulting in lactate accumulation. Lactate fuels lactylation modifications (e.g., histone H3K18la and the glycolytic enzymes ALDOA at K330 and GAPDH at K184), which promote the expression of proinflammatory genes (e.g., NLRP3 and IL-1β) and inflammasome activation. Concurrently, mitochondrial TCA cycle enzymes (e.g., IDH at K400 and HADHA at K166) undergo lactylation, impairing oxidative metabolism and exacerbating mitochondrial dysfunction. This process creates a vicious cycle: metabolic reprogramming reduces cardiac energy production, and lactylation amplifies inflammation and mitochondrial damage, ultimately contributing to myocardial dysfunction. ALDOA, aldolase A; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IDH, isocitrate dehydrogenase; HADHA, hydroxyacyl-CoA dehydrogenase; GSDMD, gasdermin D; TLR, Toll-like receptor; TCA, tricarboxylic acid cycle

Fig. 3. Mitochondrial–lactylation–calcium axis in sepsis-induced cardiomyopathy. Pathogen infection activates the NF-κB signaling pathway, triggering the release of inflammatory cytokines that induce oxidative stress and disrupt the tricarboxylic acid (TCA) cycle. This cascade depletes ATP and increases reactive oxygen species (ROS) levels. Concurrently, lactate increases p300-mediated histone lactylation, repressing mitochondrial biogenesis genes. Intracellular acidosis activates the Na⁺/H⁺ exchanger, causing Na⁺ influx; subsequent Na⁺ overload drives the Na⁺/Ca²⁺ exchanger (NCX) to the reverse mode, resulting in cytosolic Ca²⁺ accumulation. ROS-oxidized ryanodine receptor 2 (RyR2) further exacerbates sarcoplasmic reticulum Ca²⁺ leakage. The downregulation of β-adrenergic signaling inhibits L-type Ca²⁺ channel (DHPR) activity and SERCA2a activity. Collectively, Ca²⁺ mishandling and bioenergetic failure impair actin–myosin cross-bridging, leading to systolic and diastolic dysfunction. DHPR, dihydropyridine receptor; MCT, monocarboxylate transporter; NCX, Na⁺/Ca²⁺ exchanger; NHE, Na⁺/H⁺ exchanger; RyR2, ryanodine receptor 2; SERCA2a, SR Ca²⁺-ATPase; TCA, tricarboxylic acid cycle