Various cardiovascular diseases show a high occurrence of au

Various cardiovascular diseases show a high occurrence of autophagosomes. Whereas basal autophagy is required for the proper functioning of cardiomyocytes [82], the deletion of Atg5 gene in myocardium shows a high risk of cardiomyopathy [83]. Hamacher et al. observed that an upregulation of Bnip3, a mitochondrial protein, stimulates apoptotic cell death in cardiomyocytes. Its activation elevates autophagy that counteracts the apoptotic cell death by diminishing it [84]. Additionally, Munteanu et al. have recently identified VMA21 as a chaperone of V-ATPase, which facilitates proton pump and acidifies the organelles. Mutation in VMA21 increases the lysosomal pH, and therefore affects the final autophagic degradation and accumulation of autophagic debris. This forms the basis of many cardiac diseases, and hence loss of function of VMA21 gene has been characterized as one of the reasons for a cardiac disease linked through disrupted autophagy [85]. Recently, the role of small RNAs in cardiovascular diseases has also emerged to be promising. For instance, overexpression of miR-199a evoked cardiac myopathy by suppressing the autophagy through mTOR activation. This finding was further validated by the accumulation of p62 and decrease in lipidation of LC3-II with miR-199a overexpression [86]. The damaging role of autophagy is also very fascinating. The ischemic heart disease results in elevated levels of calcium in the cells, a potent activator of autophagy. The calcium mobilizing factors, such as ATP, ionomycin, and thapsigargin, inhibit mTOR, resulting in the accumulation of autophagosomes in a Beclin-1- and Atg7-mediated manner [87]. ROS is also produced during ischemic heart disease, which is a potent activator of autophagy. Moreover, LPS treatment in cardiomyocytes resulted in an increase in both autophagy and ROS levels in newborns [88]. Some studies have also pointed that down-regulation of Beclin1 and 3MA treatment caused reduced cell death in I/R cardiomyocytes [89].
Neurodegenerative disorders: the autophagic wiring As neurons are post-mitotic PI-3065 australia and are unable to undergo cytokinesis, aggregated proteins cannot be diluted by cell division. Hence, the common basis of neurodegenerative disease that portrays the accumulation of abnormal protein aggregates inside the neuronal cells can be avoided through autophagic degradation. Thus, activation of autophagy plays a critical role in neurodegenerative therapeutics providing an enthralling platform in the field of medical science [90].
Conclusion The discovery of autophagy has emerged as a major breakthrough in both physiological and pathological conditions. Studies in various models and genetic approach have clearly pointed out the implications of lysosomes in diverse diseases, including neurodegenerative diseases, cancer, aging, heart diseases, lysosomal disorders, diabetes, and obesity. We aimed to provide a better understanding of how autophagy may contribute a new perspective to human diseases (Fig. 2) (Table 1). The impact of autophagic molecular mechanisms on diseases provided a surprising, sometimes contradictory, view of the autophagic effect. In a recent experiment it showed that, genetic manipulation of the Atg5 gene with loxP sequences before exon 3 in mice showed worsening of the clinical manifestations associated with Pompe disease [119]. Thus, the activators and inhibitors of autophagy have become an exciting area for the drug development with the hope that modulating autophagic pathway could be a useful approach for the treatment of diseases. Certainly, the impact of autophagy on various diseases has shown promising results and become the new arena of research. Despite the role of autophagy in diseases, there are still some areas that need to be resolved. Moreover, the precise role of autophagy has still not been explored. Many experiments have shown that autophagy is either diminished or activated during a disease. But what is the exact process of autophagy by which this organelle regulates the progression of the disease? What is the basis of such differences in response and what extra studies should be undertaken to nullify these differences? Based on what we have reviewed, we hope that we have been able to provide a comprehensive view to reveal the role of autophagic modulators in diseases, apart from the apoptotic drugs, thus opening a new horizon in the treatment of lysosomal diseases.