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

Abstract

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.

Keywords: FUN14 domain-containing 1; Inflammation; Mitochondrial unfolded protein response; Mitophagy; Septic cardiomyopathy.