Unraveling the mitochondrial–lysosomal crosstalk: a new frontier in sepsis-induced acute lung injury

Abstract Background Sepsis-induced acute lung injury (S-ALI) and sepsis-associated acute respiratory distress syndrome (ARDS) remain major contributors to respiratory failure and mortality in critically ill patients. Mitochondrial dysfunction and lysosomal impairment are implicated in septic organ injury, but their functional interdependence remains incompletely understood. This review asked whether disruption of mitochondria–lysosome crosstalk provides an integrated framework linking bioenergetic failure, defective organelle quality control, immune dysregulation, regulated cell death, and alveolar–capillary barrier injury in S-ALI. Methods A structured literature search was conducted in PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar for articles published from January 1, 2000, to December 31, 2025. Search terms addressed mitochondria, lysosomes, mitochondria–lysosome crosstalk, mitophagy, lysosomal dysfunction, sepsis, septic shock, acute lung injury, and ARDS. Eligible evidence included peer-reviewed original studies, mechanistic investigations, and authoritative reviews relevant to sepsis, organelle biology, and lung injury; reference lists of key articles were also screened. Evidence was qualitatively appraised across four levels: general cell biology, experimental sepsis, lung-specific models or pulmonary cell types, and human or translational relevance. Findings were synthesized narratively; no meta-analysis or statistical testing was performed. Results The search identified a heterogeneous evidence base dominated by mechanistic and preclinical studies. General cell biology supports dynamic mitochondria–lysosome contact sites, metabolic and ion coupling, and lysosome-dependent mitophagy. In experimental sepsis and lung injury models, disruption of this axis is associated with mitochondrial reactive oxygen species accumulation, mtDNA release, impaired autophagic flux, inflammasome activation, inflammatory amplification, regulated cell death, and alveolar–capillary barrier dysfunction. However, direct causal evidence in pulmonary cell types and human disease remains limited, and no crosstalk-centered biomarker or therapeutic target is validated for routine clinical use. Candidate strategies include restoring mitochondrial quality control, lysosomal acidification and biogenesis, autophagic flux, and regulators such as TFEB and TBC1D15. Conclusions Mitochondria–lysosome crosstalk is a compelling organizing framework for S-ALI, but its clinical relevance requires further validation. Priorities include cell-type-specific studies, temporal mapping, human biospecimen validation, spatial multi-omics, and biomarker-guided patient stratification.