Mitochondrial unfolded protein response, mitophagy and other mitochondrial quality control mechanisms in heart disease and aged heart

Svaguša, Tomo; Martinić, Mislav; Martinić, Matea; Kovačević, Lucija; Šepac, Ana; Miličić, Davor; Bulum, Joško; Starčević, Boris; Sirotković-Skerlev, Maja; Seiwerth, Fran; Kulić, Ana; Sedlić, Filip

doi:10.3325/cmj.2020.61.126

Cited by 29 publications

(26 citation statements)

References 106 publications

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“…One of the key considerations is the relationship between mitophagy and UPR mt [ 69 , 70 ]. As discussed above, UPR mt appears to be activated prior to mitophagy induction [ 71 ]. As endogenous UPR mt cannot completely repair mitochondrial damage, mitophagy activation is an inevitable consequence under stress conditions, regardless of UPR mt activation.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…UPRmt is of great benefit to the preservation of ATP production, reduction of mtROS accumulation, and inhibition of mitochondria-mediated cell death, and showed a protective effect in chronic and acute cardiac injury ( 77 ). Activating transcription factor associated with stress-1 (ATFS-1), an UPRmt-inducing transcription factor, was showed to preserve ATP production by promoting the assembly and function of oxidative phosphorylation components during mitochondrial stress ( 78 ).…”

Section: Dysregulation Of Mitochondrial Proteostasis In Heart Failurementioning

confidence: 99%

Mitochondrial dysfunction in heart failure and its therapeutic implications

Liu

Pan

et al. 2022

Front. Cardiovasc. Med.

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The ATP consumption in heart is very intensive to support muscle contraction and relaxation. Mitochondrion is the power plant of the cell. Mitochondrial dysfunction has long been believed as the primary mechanism responsible for the inability of energy generation and utilization in heart failure. In addition, emerging evidence has demonstrated that mitochondrial dysfunction also contributes to calcium dysregulation, oxidative stress, proteotoxic insults and cardiomyocyte death. These elements interact with each other to form a vicious circle in failing heart. The role of mitochondrial dysfunction in the pathogenesis of heart failure has attracted increasing attention. The complex signaling of mitochondrial quality control provides multiple targets for maintaining mitochondrial function. Design of therapeutic strategies targeting mitochondrial dysfunction holds promise for the prevention and treatment of heart failure.

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“…Mitochondria and endoplasmic reticulum (ER) in cardiomyocytes are overrepresented organelles to co-ordinate the increased metabolic demands and maintain active calcium stores for smooth flow. Endoplasmic reticulum and mitochondria quality control circuits are also integral to cardiac function, and deregulation of these pathways are strongly implicated in cardiac diseases including heart failure [57][58][59][60][61][62][63]. ECM remodeling is emerging to coincide with metabolic rewiring in cardiomyocytes and matrixguided control of mitochondrial function in cardiomyocytes is seen as a potential therapeutic target in cardiac fibrosis, repair, regeneration and tissue engineering [64].…”

Section: Abortive Cellular Homeostasis Rebalancing In Cardiac Fibrosimentioning

confidence: 99%

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

Sharma¹,

Kaushal²,

Rawat³

et al. 2021

Extracellular Matrix - Developments and Therapeutics

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Diverse internal and external pathologic stimuli can trigger cellular stress response pathways (CSRPs) that are usually counteracted by intrinsic homeostatic machinery, which responds to stress by initiating complex signaling mechanisms to eliminate either the stressor or the damaged cells. There is growing evidence that CSRPs can have context-dependent homeostatic or pathologic functions that may result in tissue fibrosis under persistence of stress. CSRPs can drive intercellular communications through exosomes (trafficking and secretory pathway determinants) secreted in response to stress-induced proteostasis rebalancing. The injured tissue environment upon sensing the stress turns on a precisely orchestrated network of immune responses by regulating cytokine-chemokine production, recruitment of immune cells, and modulating fibrogenic niche and extracellular matrix (ECM) cross-talk during fibrotic pathologies like cardiac fibrosis, liver fibrosis, laryngotracheal stenosis, systemic scleroderma, interstitial lung disease and inflammatory bowel disease. Immunostimulatory RNAs (like double stranded RNAs) generated through deregulated RNA processing pathways along with RNA binding proteins (RBPs) of RNA helicase (RNA sensors) family are emerging as important components of immune response pathways during sterile inflammation. The paradigm-shift in RNA metabolism associated interactome has begun to offer new therapeutic windows by unravelling the novel RBPs and splicing factors in context of developmental and fibrotic pathways. We would like to review emerging regulatory nodes and their interaction with CSRPs, and tissue remodeling with major focus on cardiac fibrosis, and inflammatory responses underlying upper airway fibrosis.

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Mitochondrial unfolded protein response, mitophagy and other mitochondrial quality control mechanisms in heart disease and aged heart

Cited by 29 publications

References 106 publications

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

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

Mitochondrial dysfunction in heart failure and its therapeutic implications

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

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