ReviewBnip3 in mitophagy: Novel insights and potential therapeutic target for diseases of secondary mitochondrial dysfunction
Introduction
Bnip3, encoded by the BNIP3 gene at human chromosome 10q26.3, was first known as “NIP3” and considered to belong to the Bcl-2 family of cell death-regulating factors, which is an atypical BH3 domain only containing members of the Bcl2 family of proteins [1], [2]. Bnip3 is extensively expressed in various cells and is involved in multiple cellular functions via participation in numerous cellular signaling pathways, including mitochondrial dysfunction, mitochondrial autophagy (mitophagy), and cell apoptosis [3], [4], [5], [6]. Furthermore, as a transcriptional target in response to specific dysfunctional mitochondria, Bnip3 primarily regulates mitochondrial fragmentation and mitophagy via interaction with microtuble-associated protein light chain 3 (LC-3) and its related molecular receptors [7], [8].
Growing evidence has supported Bnip3′s association with the process of dysfunctional mitochondria and mitophagy [9] and attests to a strong relationship between Bnip3 and mitochondrial morphology. More specifically, overexpression of the BNIP3 gene has been found to result in the loss of mitochondrial membrane potential (ΔΨm) and mitochondrial permeability transition pore (mPTP) opening in cardiomyocytes, which, in turn, causes aberrant mitochondrial function and cardiac cell death [10]. Conversely, the bolstering of the homeostasis of the mitophagy process can be prompted through the inhibition of BNIP3 gene expression in cardiac myocytes, which decreases mPTP opening, rescues ΔΨm level, and suppresses mitochondrial perturbation [10]. A similar relationship can be seen in the way Bnip3 precipitates cell apoptosis and death in cardiomyocytes and hepatocytes, and how, Bnip3 deficiency, in contrast, confers a decidedly reduced risk of hepatic and cardiovascular disease [10], [11], [12], [13]. As can be seen, the overall findings from Bnip3 studies lend credibility to the hypothesis that Bnip3 figures significantly in the disorders of mitophagy homeostasis and diseases of secondary mitochondrial dysfunction.
The disorders of mitophagy homeostasis imply that abnormal fission and/or fusion of mitochondria, along with mitochondrial dysfunction, is involved in cell apoptosis and death [9], [14]. PTEN-induced kinase-1 (PINK1) and Parkin were previously considered to be the general signaling pathways for the mitophagy process [15]. As a serine-threonine kinase, PINK1 is imported into mitochondria, cleaved by the inner membrane protease presenilin-associated rhomboid-like (PARL), released into the cytosol, and degraded by the proteasome [15]. If less PINK1 is imported into mitochondria as a result of mitochondrial depolarization, it stabilizes on the outer mitochondrial membrane (OMM) and then recruits Parkin to mitochondria. This eventually leads to the clearance of depolarized mitochondria and initiates the mitophagy process [16]. Bnip3 has been implicated in mitophagy in different pathophysiological conditions, wherein Bnip3 manipulates many receptors for the incorporation of mitochondria into autophagosomes [3], [12], [17]. Therefore, the investigation of the regulatory mechanisms involved in the maintenance of Bnip3-mediated mitophagy homeostasis is of great significance for the prevention and therapy of diseases of secondary mitochondrial dysfunction.
Recently, Bnip3 has gained much attention due to its potential role in mitophagy and diseases of secondary mitochondrial dysfunction [18], [19]. Despite the emerging knowledge concerning Bnip3′s involvement in dysfunctional mitochondria, the regulatory mechanisms of Bnip3 in mitophagy are still poorly understood. We therefore aimed to review the recent investigations into the molecular structure and cell biology of Bnip3, discuss the roles of Bnip3 in mitochondrial dysfunction and disorders of mitophagy homeostasis, and further provide a framework to explain how Bnip3 plays a pathogenic role in diseases of secondary mitochondrial dysfunction, including in cardiac hypertrophy, hepatocellular carcinoma (HCC), and non-alcoholic fatty liver disease (NAFLD). Further research into the regulatory mechanisms of Bnip3 actions in mitochondrial dysfunction and mitophagy could lead to the development of novel therapeutic platforms for combatting these diseases of secondary mitochondrial dysfunction.
Section snippets
Description of the structure, function, and expression of Bnip3
Originally, B-cell leukemia/lymphoma 2 (BCL2) family was identified by chromosomal translocations that activated BCL2 gene expression, although this family was later identified through their composition of a series of shared BCL2 homology (BH) motifs (BH1, BH2, BH3, and BH4) [20]. The general structure of members in this family consists of a hydrophobic α-helix surrounded by amphipathic α-helices. Importantly, BH3, functioning as a protein-protein interaction mediator, is the only motif that is
The destructive role of Bnip3 on mitochondrial autophagy
It is well established that the abnormal development of mitochondrial autophagy (mitophagy) is the key contributor to numerous diseases, and multiple studies of abnormal mitophagy have resulted in the further identification of Bnip3 expression and/or activity in mitochondrial dysfunction [5], [36], [37]. The bulk of relevant research has demonstrated that Bnip3 is indeed a significant contributor and is strongly associated with mitophagy [18]. After autophagic stimulation, Bnip3 causes
Bnip3 is involved in mitophagy-induced cardiac hypertrophy
Growing evidence demonstrates that cardiac hypertrophy, especially irreversible ventricular remodeling, is the primary culprit for the development of heart failure [11], [83]. The heart is a vital organ that returns or pumps blood through the blood vessels of the circulatory system. When an increase in the thickness of the cardiomyocytes without a corresponding increase in ventricular size occurs with the heart under ischemic conditions, the cardiomyocytes will proliferate irrepressibly, and
Bnip3 promotes the development of hepatocellular carcinoma (HCC) by provoking mitophagy disorder
A strong association between Bnip3 and hepatocellular carcinoma has been widely acknowledged (HCC) [13], [97]. A massive epigenetic regulation investigation confirmed that the BNIP3 gene is closely linked with HCC induced by mitophagy [13], [97]. Multiple in vitro and in vivo experiments have further demonstrated that Bnip3 is intimately related to the regulation of transcription activity by methylation of promoter regions, which causes HCC-related gene silencing or abnormalities in the
Bnip3 is involved in the process of non-alcoholic fatty liver disease induced by mitophagy
Recently, incidence rates for the elderly population of all major racial and ethnic populations have increased substantially, while growth rates of obesity and metabolic syndrome suggest that the prevalence of NAFLD will continue to rise [101]. NAFLD is a metabolic syndrome characterized by the disorder of hepatic lipid homeostasis and intrahepatic accumulation of a large amount of lipid [111]. Chronic liver disease, along with its progression to NAFLD, has become a major socio-economic burden.
Conclusions and perspectives
This review summarizes the crucial roles and underlying mechanisms of Bnip3 in mitophagy and diseases of secondary mitochondrial dysfunction, including cardiac hypertrophy, HCC, and NAFLD. Bnip3 manipulates the morphology, function, and homeostasis of fission and fusion on mitochondria through various signaling pathways [11], [12], [80], [96], [122]. It also regulates mitochondrial dysfunction, mitochondrial fragmentation, mitophagy, cell apoptosis, and the development of lipid disorder
Declaration of Competing Interest
The authors declare that they have no conflicts of interests. The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Acknowledgments
This work is funded by the National Natural Science Foundation of China (NO. 81503074).
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These authors contributed equally to this work.