PGAM5 and serum lipopolysaccharide activity: The three main findings of the present study can be summarized as follows: 1) Pgam5 activation is an initial upstream signal in endotoxemia-related myocardial depression through a mechanism involving PHB2 dephosphorylation; 2) LPS-induced, Pgam5-dependent PHB2 dephosphorylation impedes PHB2 retention in mitochondria, which inactivates stress-related mitophagy and UPRmt; 3) Aberrant mitophagy and UPRmt are associated with mitochondrial dysfunction and cardiomyocyte death, which correlate with disrupted myocardial structure and function characteristic of septic cardiomyopathy.