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.

Targeting Mediators of Inflammation in Heart Failure: A Short Synthesis of Experimental and Clinical Results

“…Two defensive mechanisms, mitophagy and the mitochondrial unfolded protein response, counteract mitochondrial deterioration. Urolithin A, a mitophagy inducer, diminishes systemic inflammation mediated cardiac depression, improving mitochondrial function [ 22 ]. In mice, deletion of the regulatory FUN14 domain-containing protein 1 (FUNDC1) inhibits calcium influx from the cytoplasm through the inositol 1,4,5-trisphosphate receptor type 2 (IP 3 R 2 ) and maintains mitochondrial integrity.…”

Novel Insights Into the Potential Mechanisms of N6-Methyladenosine RNA Modification on Sepsis-Induced Cardiovascular Dysfunction: An Update Summary on Direct and Indirect Evidences

“…The heart is rich in mitochondria, which are involved in both energy provision and intracellular calcium regulation; consequently, the degree of mitochondrial dysfunction is tightly linked to SICD and the prognosis of this condition ( Lin et al, 2020a ; Shi et al, 2021a ; Wang et al, 2021a ). The activities of complexes I and II of the mitochondrial respiratory chain were diminished in the hearts from animals with sepsis ( Piel et al, 2007 ; Neviere et al, 2016 ), and this might be due to the detrimental effects of sepsis mediators such as NO, TNF-α, IL-1β, etc.…”

“…In septic rats, UPRmt is known to be downregulated under sepsis attacks ( Shen et al, 2021 ). Enhancement of endogenous UPRmt through oligomycin administration reduced sepsis-mediated mitochondrial injury and myocardial dysfunction through mitophagy ( Wang et al, 2021a ).…”

The Emerging Role of FUNDC1-Mediated Mitophagy in Cardiovascular Diseases

“…Wang et al 's work showed that activation of FUNDC1-mediated mitophagy by UA, a mitophagy inducer, attenuated SICM in LPS-treated mice model (Wang et al, 2021). They found that the elevation of the levels of cardiac injury markers by LPS treatment is inhibited by UA administration in control mice but not in cardiomyocyte-specific FUNDC1 knockout mice (Wang et al, 2021).…”

“…Wang et al 's work showed that activation of FUNDC1-mediated mitophagy by UA, a mitophagy inducer, attenuated SICM in LPS-treated mice model (Wang et al, 2021). They found that the elevation of the levels of cardiac injury markers by LPS treatment is inhibited by UA administration in control mice but not in cardiomyocyte-specific FUNDC1 knockout mice (Wang et al, 2021). The expression of mtUPR-related genes is significantly upregulated when FUNDC1 is deficient in LPS-treated heart, indicating that mtUPR is activated when mitophagy is blocked in response to LPS treatment (Wang et al, 2021).…”