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Anthracyclines such as doxorubicin (Dox) are widely used to treat a variety of adult and childhood cancers, however, a major limitation to many of these compounds is their propensity for inducing heart failure. A naturally occurring polyphenolic compound such as Ellagic acid (EA) has been shown by our laboratory to mitigate the cardiotoxic effects of Dox, however, the effects of EA on cancer cell viability have not been established. In this study, we explored the effects of EA alone and in combination with Dox on cancer cell viability and tumorigenesis. Herein, we show that EA induces cell cycle exit and reduces proliferation in colorectal cancer (HCT116) and breast adenocarcinoma cells (MCF7). We show that EA promotes cell cycle exit by a mechanism that inhibits mitochondrial dynamics protein Drp-1. EA treatment of HCT116 and MCF7 cells resulted in a hyperfused mitochondrial morphology that coincided with mitochondrial perturbations including loss of mitochondrial membrane potential, impaired respiratory capacity. Moreover, impaired mitochondrial function was accompanied by a reduction in cell cycle and proliferation markers, CDK1, Ki67, and Cyclin B. This resulted in a reduction in proliferation and widespread death of cancer cells. Furthermore, while Dox treatment alone promoted cell death in both HCT116 and MCF7 cancer cell lines, EA treatment lowered the effective dose of Dox to promote cell death. Hence, the findings of the present study reveal a previously unreported anti-tumor property of EA that impinges on mitochondrial dynamics protein, Drp-1 which is crucial for cell division and tumorigenesis. The ability of EA to lower the therapeutic threshold of Dox for inhibiting cancer cell growth may prove beneficial in reducing cardiotoxicity in cancer patients undergoing anthracycline therapy.

Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases characterized by lysosomal enzyme deficiency. The cardiac phenotype includes cardiomyopathy with eventual heart failure. Lysosome-mediated degradation processes, such as autophagy, maintain cellular homeostasis by discarding cellular debris and damaged organelles. Under stress, the transcription factor EB (TFEB) moves into the nucleus to activate transcription of lysosome biogenesis and autophagic proteins. In this issue of the JCI, Ikeda et al. report on their exploration of the signaling pathway involved with regulating lysosomal proteins specifically in the heart. The researchers generated a mouse model for LSD that was restricted to cardiac tissue. Unexpectedly, modulation of TFEB alone was insufficient to fully rescue the underlying clearance defect in lysosomal-associated disorders. The authors identified the Yes-associated protein (YAP)/TFEB signaling pathway as a key regulator of autophagosomes. These findings suggest that undigested autophagosomes accumulate and result in the cell death and cardiac dysfunction observed with LSD.

Contact between organelles such as the mitochondria (Mito) and endoplasmic reticulum (ER) is crucial to coordinate vital cellular homeostatic processes. Here we discuss recent work showing that Mito-ER proximity is regulated by heterotypic complexes between the F-actin polymerizing protein Diaphanous-1) and the mitochondrial dynamics protein Mitofusin 2, which confers increased susceptibility to ischemia/reperfusion injury.

Significance We provide new, exciting evidence for a previously unidentified signaling pathway that mechanistically links mitochondrial respiratory chain defects to necrosis and heart failure induced by the chemotherapy agent doxorubicin (DOX). We specifically show that DOX disrupts protein complexes between the key respiratory chain proteins, including uncoupling protein 3 and cytochrome c oxidase, resulting in abnormal mitochondrial respiration and necrosis through a mechanism contingent on Bcl-2-like 19kDa-interacting protein 3 (Bnip3). Perhaps most compelling is our finding that inhibiting Bnip3 completely abrogated the cardiotoxic effects of DOX. These exciting findings have important clinical implications not only for preventing heart failure by targeting Bnip3 in cancer patients undergoing chemotherapy, but also for understanding the pathogenesis of other diseases in which mitochondrial function is compromised. Doxorubicin (DOX) is widely used for treating human cancers, but can induce heart failure through an undefined mechanism. Herein we describe a previously unidentified signaling pathway that couples DOX-induced mitochondrial respiratory chain defects and necrotic cell death to the BH3-only protein Bcl-2-like 19kDa-interacting protein 3 (Bnip3). Cellular defects, including vacuolization and disrupted mitochondria, were observed in DOX-treated mice hearts. This coincided with mitochondrial localization of Bnip3, increased reactive oxygen species production, loss of mitochondrial membrane potential, mitochondrial permeability transition pore opening, and necrosis. Interestingly, a 3.1-fold decrease in maximal mitochondrial respiration was observed in cardiac mitochondria of mice treated with DOX. In vehicle-treated control cells undergoing normal respiration, the respiratory chain complex IV subunit 1 (COX1) was tightly bound to uncoupling protein 3 (UCP3), but this complex was disrupted in cells treated with DOX. Mitochondrial dysfunction induced by DOX was accompanied by contractile failure and necrotic cell death. Conversely, shRNA directed against Bnip3 or a mutant of Bnip3 defective for mitochondrial targeting abrogated DOX-induced loss of COX1-UCP3 complexes and respiratory chain defects. Finally, Bnip3 ⁻/⁻ mice treated with DOX displayed relatively normal mitochondrial morphology, respiration, and mortality rates comparable to those of saline-treated WT mice, supporting the idea that Bnip3 underlies the cardiotoxic effects of DOX. These findings reveal a new signaling pathway in which DOX-induced mitochondrial respiratory chain defects and necrotic cell death are mutually dependent on and obligatorily linked to Bnip3 gene activation. Interventions that antagonize Bnip3 may prove beneficial in preventing mitochondrial injury and heart failure in cancer patients undergoing chemotherapy.

Mitofusins reside on the outer mitochondrial membrane and regulate mitochondrial fusion, a physiological process that impacts diverse cellular processes. Mitofusins are activated by conformational changes and subsequently oligomerize to enable mitochondrial fusion. Here, we identify small molecules that directly increase or inhibit mitofusins activity by modulating mitofusin conformations and oligomerization. We use these small molecules to better understand the role of mitofusins activity in mitochondrial fusion, function, and signaling. We find that mitofusin activation increases, whereas mitofusin inhibition decreases mitochondrial fusion and functionality. Remarkably, mitofusin inhibition also induces minority mitochondrial outer membrane permeabilization followed by sub-lethal caspase-3/7 activation, which in turn induces DNA damage and upregulates DNA damage response genes. In this context, apoptotic death induced by a second mitochondria-derived activator of caspases (SMAC) mimetic is potentiated by mitofusin inhibition. These data provide mechanistic insights into the function and regulation of mitofusins as well as small molecules to pharmacologically target mitofusins. Mitofusins regulate mitochondrial fusion. Here the authors identify small molecules that activate or inhibit mitofusins’ activity and modulate mitochondrial fusion and functionality. Inhibition of mitochondrial fusion promotes minority MOMP, caspase-3/7 activation, and DNA damage.

Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases characterized by lysosomal enzyme deficiency. The cardiac phenotype includes cardiomyopathy with eventual heart failure. Lysosomemediated degradation processes, such as autophagy, maintain cellular homeostasis by discarding cellular debris and damaged organelles. Under stress, the transcription factor EB (TFEB) moves into the nucleus to activate transcription of lysosome biogenesis and autophagic proteins. In this issue of the JCI, Ikeda et al. report on their exploration of the signaling pathway involved with regulating lysosomal proteins specifically in the heart. The researchers generated a mouse model for LSD that was restricted to cardiac tissue. Unexpectedly, modulation of TFEB alone was insufficient to fully rescue the underlying clearance defect in lysosomal-associated disorders. The authors identified the Yes-associated protein (YAP)/TFEB signaling pathway as a key regulator of autophagosomes. These findings suggest that undigested autophagosomes accumulate and result in the cell death and cardiac dysfunction observed with LSD.

The heart relies on mitochondria-derived energy production for continuous contraction and relaxation; therefore, the maintenance of a pool of healthy mitochondria is essential for sustaining normal cardiac performance. Mitophagy serves as a critical process for maintaining mitochondrial quality control and involves the PTEN-induced kinase 1/Parkin (Pink1/Parkin) pathway and autophagosomes labeled with the autophagy proteins autophagy-related 7 (ATG) and light chain 3 (LC3). In this issue of the JCI, Saito and colleagues identify an alternative pathway for mitophagy that utilizes the serine/threonine protein kinase Unc-51-like kinase 1 (Ulk1) and the small GTPase Rab9 to clear damaged mitochondria independently of conventional autophagy proteins. Together, the results of this study reveal that Ulk1 phosphorylation of Rab9 at serine 179 is critical for alternative mitophagy and cardioprotection under energy stress conditions.

Despite the progress that has been made over the past two decades in cardiovascular research, heart failure remains a major cause of morbidity and mortality worldwide. Insight into the cellular and molecular mechanisms that underlie the heart failure in individuals with ischemic heart disease have identified defects in cellular processes that govern autophagy, apoptosis and necrosis as a prevailing underlying cause. Indeed, programmed cell death of cardiac cells by apoptosis or necrosis is believed to involve the intrinsic mitochondrial pathway and/or extrinsic death receptor pathway by certain Bcl-2 family members as well as components of the TNFα signaling pathway. In this review, we discuss recent advances in the molecular signaling factors that govern cardiac cell fate under normal and disease conditions.

Advanced glycation end-products (AGEs) are formed by the non-enzymatic glycation of proteins, lipids, and nucleic acids due to the consumption of high-carbohydrate diets; their production is also promoted by a sedentary lifestyle as well as cigarette smoking. Elevated levels of AGEs in the circulatory system and internal organs of the body are commonly observed in a number of cardiovascular diseases such as hypertension, diabetes, atherosclerosis, coronary artery disease, aortic aneurysm, atrial fibrillation, myocardial infarction, and heart failure, which are associated with the development of oxidative stress and myocardial inflammation. The adverse effects of AGEs on the cardiovascular system are elicited by both non-receptor mechanisms involving the cross-linking of extracellular and intracellular proteins, and by receptor-mediated mechanisms involving the binding of AGEs with advanced glycation end-product receptors (RAGEs) on the cell membrane. AGE–RAGE interactions along with the cross-linking of proteins promote the generation of oxidative stress, the production of inflammation, the occurrence of intracellular Ca2+-overload, and alterations in the extracellular matrix leading to the development of cardiovascular dysfunction. AGEs also bind with two other protein receptors in the circulatory system: soluble RAGEs (sRAGEs) are released upon the proteolysis of RAGEs due to the activation of matrix metalloproteinase, and endogenous secretory RAGEs (esRAGEs) are secreted as a spliced variant of endogenous RAGEs. While the AGE–RAGE signal transduction axis serves as a pathogenic mechanism, both sRAGEs and esRAGEs serve as cytoprotective interventions. The serum levels of sRAGEs are decreased in ischemic heart disease, vascular disease, and heart failure, as well as in other cardiovascular diseases, but are increased in chronic diabetes and renal disease. Several interventions which can reduce the formation of AGEs, block the AGE–RAGE axis, or increase the levels of circulating sRAGEs have been shown to exert beneficial effects in diverse cardiovascular diseases. These observations support the view that the AGE–RAGE axis not only plays a critical role in pathogenesis, but is also an excellent target for the treatment of cardiovascular disease.

ObjectiveWe aimed to characterise the association between inflammatory bowel disease (IBD) and IBD medications and risk of cardiac arrhythmia.Design, setting and participantsIn a retrospective population-based study using the University of Manitoba IBD Epidemiology Database (Manitoba, Canada) from 1984 to 2018, we identified 10 992 IBD cases and 102 875 matched controls.AnalysisArrhythmia risk in IBD was adjusted for the presence of comorbidities of the Charlson Comorbidity Index. The effect of IBD medications on the development of arrhythmia was assessed in a nested cohort study of individuals with IBD. Cases were censored at the date of first database identification of a diagnosis of heart failure or myocardial infarction.ResultsThe cohort was 48.5% Crohn’s disease and 51.5% ulcerative colitis, and 80.5% were incident cases. The median age of incident cases at IBD diagnosis was 35 (IQR, 25 to 49). The median age at arrhythmia diagnosis for persons with IBD was 69 years (IQR, 59 to 77) and for controls 69 years (IQR, 59 to 78). Persons diagnosed with IBD were more likely than controls (HR 1.51; 95% CI, 1.30 to 1.76) to develop arrhythmia. Persons within their sixth decade or younger had increased risk of arrhythmia. When controlling for comorbidities, the significant association between IBD and arrhythmia remains. Medications including 5-aminosalicylates, thiopurines and tumour necrosis factor-α inhibitors were not associated with arrhythmia.ConclusionsPersons with IBD have a higher risk of arrhythmia prior to a diagnosis with heart disease. Use of IBD medications was not associated with risk of arrhythmia.