Mitophagy coordinates the mitochondrial unfolded protein response to attenuate inflammation-mediated myocardial injury

Mitochondrial dysfunction is a fundamental challenge in septic cardiomyopathy. Mitophagy and the mitochondrial unfolded protein response (UPR(mt)) are the predominant stress-responsive and protective mechanisms involved in repairing damaged mitochondria. Although mitochondrial homeostasis requires the coordinated actions of mitophagy and UPR(mt), their molecular basis and interactive actions are poorly understood in sepsis-induced myocardial injury. Our investigations showed that lipopolysaccharide (LPS)-induced sepsis contributed to cardiac dysfunction and mitochondrial damage. Although both mitophagy and UPR(mt) were slightly activated by LPS in cardiomyocytes, their endogenous activation failed to prevent sepsis-mediated myocardial injury. However, administration of urolithin A, an inducer of mitophagy, obviously reduced sepsis-mediated cardiac depression by normalizing mitochondrial function. Interestingly, this beneficial action was undetectable in cardiomyocyte-specific FUNDC1 knockout (FUNDC1(CKO)) mice. Notably, supplementation with a mitophagy inducer had no impact on UPR(mt), whereas genetic ablation of FUNDC1 significantly upregulated the expression of genes related to UPR(mt) in LPS-treated hearts. In contrast, enhancement of endogenous UPR(mt) through oligomycin administration reduced sepsis-mediated mitochondrial injury and myocardial dysfunction; this cardioprotective effect was imperceptible in FUNDC1(CKO) mice. Lastly, once UPR(mt) was inhibited, mitophagy-mediated protection of mitochondria and cardiomyocytes was partly blunted. Taken together, it is plausible that endogenous UPR(mt) and mitophagy are slightly activated by myocardial stress and they work together to sustain mitochondrial performance and cardiac function. Endogenous UPR(mt), a downstream signal of mitophagy, played a compensatory role in maintaining mitochondrial homeostasis in the case of mitophagy inhibition. Although UPR(mt) activation had no negative impact on mitophagy, UPR(mt) inhibition compromised the partial cardioprotective actions of mitophagy. This study shows how mitophagy modulates UPR(mt) to attenuate inflammation-related myocardial injury and suggests the potential application of mitophagy and UPR(mt) targeting in the treatment of myocardial stress.