The role of TBC1D15 in sepsis-induced acute lung injury: Regulation of mitochondrial homeostasis and mitophagy.

Summary

TBC1D15 expression is reduced in sepsis and its overexpression restores mitophagy, shortens pathological mitochondria–lysosome contact, and attenuates lung injury and inflammation in SI-ALI models. The protective effects are mitophagy-dependent, as pharmacologic inhibition abrogates benefit.

Key Findings

• TBC1D15 levels were decreased in sepsis patient blood, monocytes, SI-ALI mouse lungs, and MLE-12 cells.
• TBC1D15 overexpression reduced lung injury and inflammation while promoting mitophagy and mitochondrial function.
• Mitophagy inhibition with Bafilomycin A1 abrogated TBC1D15’s protective effects.
• TBC1D15 knockdown prolonged mitochondria–lysosome contact, worsening mitochondrial dysfunction and oxidative stress.

Clinical Implications

Suggests potential for mitophagy-enhancing strategies or TBC1D15-targeted approaches in sepsis-induced lung injury; clinical translation will require safety and efficacy studies.

Limitations

• Preclinical study without human interventional data
• Overexpression/viral delivery may not directly translate to clinical modalities

Future Directions

Elucidate upstream regulators of TBC1D15 in sepsis, screen small molecules to modulate TBC1D15/mitophagy, and test efficacy in large-animal models prior to clinical trials.