Mitochondrial dynamics: Orchestrating the journey to advanced age.

Aging is a degenerative process that unfortunately is an inevitable part of life and risk factor for cardiovascular disease including heart failure. Among the several theories purported to explain the effects of age on cardiac dysfunction, the mitochondrion has emerged a central regulator of this process. Hence, it is not surprising that abnormalities in mitochondrial quality control including biogenesis and turnover have such detrimental effects on cardiac function. In fact mitochondria serve as a conduit for biological signals for apoptosis, necrosis and autophagy respectively. The removal of damaged mitochondria by autophagy/mitophagy is essential for mitochondrial quality control and cardiac homeostasis. Defects in mitochondrial dynamism fission/fusion events have been linked to cardiac senescence and heart failure. In this review we discuss the impact of aging on mitochondrial dynamics and senescence on cardiovascular health. This article is part of a Special Issue entitled: CV Aging.

Autophagy in the heart: too much of a good thing?

Autophagy constitutes a catabolic process involving lysosomal degradation of damaged and redundant cytosolic components into biomolecules, via an elaborate lysosomal pathway. Autophagy is a highly regulated and evolutionary conserved process crucial for normal tissue homeostasis and cell life. Certain members of the Bcl-2 gene family, including the BH3 only protein Bnip3 regulate autophagy during cardiac stress during ischemic or hypoxic injury as means of discarding damaged mitochondria and organelles to avert cell death. Defects in the regulation of autophagy have been associated with a number of human pathologies including cancer, neurodegenerative diseases, and heart failure. Here, we discuss the molecular regulation of autophagy in the heart and cellular demise from "too much a good thing."

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs.

Analyses of Adverse Drug Reactions-Nationwide Active Surveillance Network: Canadian Pharmacogenomics Network for Drug Safety Database.

Adverse drug reactions (ADRs) are a major problem in modern medicine, representing up to the fourth-highest cause of mortality. Pharmacogenomic tests are 1 of the most promising methods to tackle the challenge of ADRs. The objective of this study was to analyze the clinical and demographic information of the pan-Canadian active surveillance network, Canadian Pharmacogenomics Network for Drug Safety (CPNDS). Information entered into the database by trained active surveillors between May 15, 2005 and May 9, 2017 was collected and analyzed. Specific data included for analysis were number of ADR reports, reports of drug use without ADRs, date of onset of ADR, suspected drugs, concomitant drugs, and fatal ADR cases. The CPNDS database consisted of 93,974 reports of medication use, including 10,475 reports of ADRs, of which 72.6% occurred in pediatric patients (≤21 years old). Self-reported ancestries were predominantly Europe (38.2%), Canada (9.6%), and East Asia (4.9%). The 5 most frequent ADRs were cutaneous ADRs, peripheral neuropathy, cardiotoxicity, central nervous system toxicity, and ototoxicity. The 5 drugs most commonly suspected to cause ADRs were methotrexate, vincristine, doxorubicin, cisplatin, and L-asparaginase. The CPNDS database is a valuable resource to identify clinical and genomic predictors of ADRs. The database also highlights our candidate ADRs for pharmacogenomic discovery research to identify additional ADR biomarkers. Additionally, the database provides information that can be used for developing strategies to prevent ADRs and raises awareness of ADRs among Canadian healthcare professionals.

The interplay between cell death signaling pathways in the heart.

To date, one of the most intriguing and compelling concepts to impact contemporary cell biology is the notion that cell fate is "programmed" or genetically controlled. Indeed, the regulation of cell fate is crucial for embryonic development, and tissue homeostasis. Given the importance of removing damaged or irreversibly injured cells from the body, it is not surprising that defects in the regulatory mechanisms that govern cell death and/or survival more generally have been implicated in a number of human pathologies including cancer, neurodegenerative diseases, and cardiac failure. Several processes involved in the regulation of cell fate through apoptosis, necrosis, and autophagy are commonly linked through the actions of certain Bcl-2 proteins that act on the mitochondrion. For example, the Bcl-2 protein Beclin-1 is actively involved in the clearance of damaged mitochondria via mitophagy, while other Bcl-2 proteins such as Bax/Bak can initiate apoptosis or necrotic signaling pathways. The overlapping and redundant nature of these proteins highlights their evolutionary importance for regulating cardiac cell survival and death during normal and disease states. Here, we explore the interrelationship between these signaling pathways and the cellular effectors that influence cardiac cell fate.

Bidirectional regulation of nuclear factor-κB and mammalian target of rapamycin signaling functionally links Bnip3 gene repression and cell survival of ventricular myocytes.

BACKGROUND: Tumor necrosis factor-α and other proinflammatory cytokines activate the canonical nuclear factor (NF)-κB pathway through the kinase IKKß. Previously, we established that IKKß is also critical for Akt-mediated NF-κB activation in ventricular myocytes. Akt activates the kinase mammalian target of rapamycin (mTOR), which mediates important processes such as cardiac hypertrophy. However, whether mTOR regulates cardiac myocyte cell survival is unknown. METHODS AND RESULTS: Herein, we demonstrate bidirectional regulation between NF-κB signaling and mTOR, the balance which determines ventricular myocyte survival. Overexpression of IKKß resulted in mTOR activation and conversely overexpression of mTOR lead to NF-κB activation. Loss of function approaches demonstrated that endogenous levels of IKKß and mTOR also signal through this pathway. NF-κB activation by mTOR was mediated by phosphorylation of the NF-κB p65 subunit increasing p65 nuclear translocation and activation of gene transcription. This circuit was also important for NF-κB activation by the canonical tumor necrosis factor-α pathway. Our previous work has shown that NF-κB signaling suppresses transcription of the death gene Bnip3 resulting in ventricular myocyte survival. Inhibition of mTOR with rapamycin decreased NF-κB activation resulting in increased Bnip3 expression and cell death. Conversely, mTOR overexpression suppressed Bnip3 levels and cell death of ventricular myocytes in response to hypoxia. CONCLUSIONS: To our knowledge, these data provide the first evidence for a bidirectional link between NF-κB signaling and mTOR that is critical in the regulation of Bnip3 expression and cardiac myocyte death. Hence, modulation of this axis may be cardioprotective during ischemia.