Editorial, see p 225Mitochondria are dynamic organelles that constantly undergo fusion and fission 5 to adapt to changes in the cellular environment. Although mitochondrial fusion allows mitochondria to maintain membrane potential by fusing depolarized mitochondria to intact ones, fission allows the segregation of unrecoverable mitochondria so that they can be eliminated by autophagy or mitophagy, a specialized form of autophagy.6 Mitochondrial fusion is critically

Background Mitochondrial autophagy is an important mediator of mitochondrial quality control in cardiomyocytes. The occurrence of mitochondrial autophagy and its significance during cardiac hypertrophy are not well understood. Methods and Results Mice were subjected to transverse aortic constriction (TAC) and observed at multiple time points up to 30 days. Cardiac hypertrophy developed after 5 days, the ejection fraction was reduced after 14 days, and heart failure (HF) was observed 30 days after TAC. General autophagy was upregulated between 1 and 12 hours after TAC but was downregulated below physiological levels 5 days after TAC. Mitochondrial autophagy, evaluated by electron microscopy, mitochondrial content, and Mito-Keima, was transiently activated around 3–7 days post-TAC, coinciding with mitochondrial translocation of Drp1. However, it was downregulated thereafter, followed by mitochondrial dysfunction. Haploinsufficiency of Drp1 abolished mitochondrial autophagy and exacerbated the development of both mitochondrial dysfunction and HF after TAC. Injection of Tat-Beclin 1, a potent inducer of autophagy, but not control peptide, on Day 7 after TAC partially rescued mitochondrial autophagy, and attenuated mitochondrial dysfunction and HF induced by pressure overload (PO). Haploinsufficiency of either drp1 or beclin 1 prevented the rescue by Tat-Beclin 1, suggesting that its effect is mediated in part through autophagy, including mitochondrial autophagy. Conclusions Mitochondrial autophagy is transiently activated and then downregulated in the mouse heart in response to PO. Downregulation of mitochondrial autophagy plays an important role in mediating the development of mitochondrial dysfunction and HF, whereas restoration of mitochondrial autophagy attenuates dysfunction in the heart during PO.

The aging population is increasing in developed countries. Since the incidence of cardiac disease increases dramatically with age, it is important to understand the molecular mechanisms through which the heart becomes either more or less susceptible to stress. Cardiac aging is characterized by the presence of hypertrophy, fibrosis, and accumulation of misfolded proteins and dysfunctional mitochondria. Macroautophagy (hereafter referred to as “autophagy”) is a lysosome-dependent bulk degradation mechanism that is essential for intracellular protein and organelle quality control. Autophagy and autophagic flux are generally decreased in aging hearts, and murine autophagy loss-of-function models develop exacerbated cardiac dysfunction that is accompanied by accumulation of misfolded proteins and dysfunctional organelles. On the other hand, stimulation of autophagy generally improves cardiac function in mouse models of protein aggregation by removing accumulated misfolded proteins, dysfunctional mitochondria, and damaged DNA, thereby improving the overall cellular environment and alleviating aging-associated pathology in the heart. Increasing lines of evidence suggest that autophagy is required for many mechanisms that mediate lifespan extension, such as caloric restriction, in various organisms. These results raise the exciting possibility that autophagy may play an important role in combating the adverse effects of aging in the heart. In this review, we discuss the role of autophagy in the heart during aging, how autophagy alleviates age-dependent changes in the heart, and how the level of autophagy in the aging heart can be restored.

Diabetic patients develop cardiomyopathy characterized by hypertrophy, diastolic dysfunction, lipotoxicity, and mitochondrial dysfunction. How mitochondrial function is regulated in diabetic cardiomyopathy remains poorly understood. Mice were fed either a normal diet (ND) or a high fat diet (HFD, 60 kcal % fat). Mitophagy, evaluated with Mito‐Keima, was increased after 3 weeks of HFD feeding (mitophagy area: 8.3% per cell with ND and 12.4% with HFD) and continued to increase after 20 weeks (p<0.05). Although we have shown recently that mitophagy during the early phase of HFD feeding is mediated by Atg7‐dependent mechanisms, the mechanisms mediating mitophagy in the heart during the chronic phase of HFD feeding remain poorly understood. Phosphorylation of ULK1 was activated and Rab9 protein level was increased in the mitochondrial fraction within 20 weeks of HFD consumption (p<0.05). By isolating adult cardiomyocytes from GFP‐Rab9 transgenic mice fed HFD, we discovered that mitochondria were sequestrated by Rab9‐positive ring‐like structures. Since ULK1 regulates Rab9‐dependent mitophagy, we fed ULK1 cKO mice with HFD for 20 weeks. In wild type (WT) mice, cardiac hypertrophy and diastolic dysfunction (EDPVR = 0.051±0.009 in ND and 0.115±0.006 in HFD) were induced after 20 weeks of HFD feeding (p<0.05). By crossing Tg‐Mito‐Keima mice with ULK1 cKO mice, we found that downregulation of ULK1 impaired mitophagy in response to ND or 20 weeks of HFD consumption (p<0.05). Deletion of ULK1 exacerbated diastolic dysfunction (EDPVR=0.115±0.006 in WT and 0.162±0.021 in ULK1 cKO, p<0.05) and even induced systolic dysfunction (ESPVR=22.74±2.13 in WT and 16.78±2.12 in ULK1 cKO, p<0.05) during HFD feeding. Electron microscopic analyses indicated that the mitochondrial cristae structure was disrupted more severely in ULK1 cKO mice with HFD feeding than control mice (p<0.05). In summary, genetic disruption of ULK1‐Rab9‐dependent mitophagy during the chronic phase of HFD feeding exacerbates mitochondrial dysfunction, thereby facilitating the development of diabetic cardiomyopathy. ULK1‐Rab9‐dependent mitophagy serves as an essential quality control mechanism for cardiac mitochondria during HFD feeding. Support or Funding Information The project was supported by AHA and NIH (5R01HL138720‐02). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

TRE reduced MI-induced cardiac remodeling and dysfunction through activation of autophagy.

Patients with heart failure (HF) are sometimes classified as malnourished, but the prognostic value of nutritional status in acute HF (AHF) remains largely unstudied. 1214 patients who were admitted to the intensive care unit between January 2000 and June 2016 were screened based on their serum albumin, lymphocyte count, and total cholesterol measures. A total of 458 HF patients were enrolled in this study. The Prognostic Nutritional Index (PNI) is calculated as 10 × serum albumin (g/dL) + 0.005 × lymphocyte count (per mm) (lower = worse). The Controlling Nutritional Status (CONUT) score is points based, and is calculated using serum albumin, total cholesterol, and lymphocyte count (range 0-12, higher = worse). Patients were divided into three groups according to PNI: high-PNI (PNI < 35, n = 331), middle-PNI (35 ≤ PNI < 38, n = 50), and low-PNI (PNI ≥ 38, n = 77). They were also divided into four groups according to CONUT score: normal-CONUT (0-1, n = 128), mild-CONUT (2-4, n = 179), moderate-CONUT (5-8, n = 127), and severe-CONUT (≥9, n = 24). The PNI, which exhibited a good balance between sensitivity and specificity for predicting in-hospital mortality [66.1 and 68.4%, respectively; area under the curve (AUC) 0.716; 95% confidence interval (CI) 0.638-0.793), was 39.7 overall, while the CONUT score was 5 overall (61.4 and 68.4%, respectively; AUC 0.697; 95% CI 0.618-0.775). A Kaplan-Meier curve indicated that the prognosis, including all-cause death, was significantly (p < 0.001) poorer in low-PNI patients than in high-PNI groups and was also significantly poorer in severe-CONUT patients than in normal-CONUT and mild-CONUT groups. A multivariate Cox regression model showed that the low-PNI and severe-CONUT categories were independent predictors of 365-day mortality [hazard ratio (HR) 2.060, 95% CI 1.302-3.259 and HR 2.238, 95% CI 1.050-4.772, respectively). Malnutrition, as assessed using both the PNI and the CONUT score, has a prognostic impact in patients with severely decompensated AHF.

Mitochondria are essential organelles that produce the cellular energy source, ATP. Dysfunctional mitochondria are involved in the pathophysiology of heart disease, which is associated with reduced levels of ATP and excessive production of reactive oxygen species. Mitochondria are dynamic organelles that change their morphology through fission and fusion in order to maintain their function. Fusion connects neighboring depolarized mitochondria and mixes their contents to maintain membrane potential. In contrast, fission segregates damaged mitochondria from intact ones, where the damaged part of mitochondria is subjected to mitophagy whereas the intact part to fusion. It is generally believed that mitochondrial fusion is beneficial for the heart, especially under stress conditions, because it consolidates the mitochondria's ability to supply energy. However, both excessive fusion and insufficient fission disrupt the mitochondrial quality control mechanism and potentiate cell death. In this review, we discuss the role of mitochondrial dynamics and mitophagy in the heart and the cardiomyocytes therein, with a focus on their roles in cardiovascular disease.

Rationale In Drosophila, the Hippo signaling pathway negatively regulates organ size by suppressing cell proliferation and survival through the inhibition of Yorkie, a transcriptional co-factor. Yes-associated protein (YAP), the mammalian homolog of Yorkie, promotes cardiomyocyte growth and survival in postnatal hearts. However, the underlying mechanism responsible for the beneficial effect of YAP in cardiomyocytes remains unclear. Objectives We investigated whether miR-206, a microRNA known to promote hypertrophy in skeletal muscle, mediates the effect of YAP upon promotion of survival and hypertrophy in cardiomyocytes. Methods and Results Microarray analysis indicated that YAP increased miR-206 expression in cardiomyocytes. Increased miR-206 expression induced cardiac hypertrophy and inhibited cell death in cultured cardiomyocytes, similar to that of YAP. Down regulation of endogenous miR-206 in cardiomyocytes attenuated YAP-induced cardiac hypertrophy and survival, suggesting that miR-206 plays a critical role in mediating YAP function. Cardiac-specific overexpression of miR-206 in mice induced hypertrophy and protected the heart from ischemia/reperfusion (I/R) injury, whereas suppression of miR-206 exacerbated I/R injury and prevented pressure overload-induced cardiac hypertrophy. miR-206 negatively regulates FoxP1 expression in cardiomyocytes and overexpression of FoxP1 attenuated miR-206-induced cardiac hypertrophy and survival, suggesting that FoxP1 is a functional target of miR-206. Conclusions YAP increases the abundance of miR-206, which in turn plays an essential role in mediating hypertrophy and survival by silencing FoxP1 in cardiomyocytes.