Mitophagy in metabolic syndrome

Abstract Metabolic syndrome (MS), a chronic and non‐communicable pathological condition, is characterized by a constellation of clinical manifestations including insulin resistance, abdominal adiposity, elevated blood pressure, and perturbations in lipid metabolism. The prevalence of MS has increased dramatically in both developed and developing countries and has now become a truly global problem. Excessive energy intake and concomitant obesity are the main drivers of this syndrome. Mitophagy, in which cells degrade damaged mitochondria through a selective form of autophagy, assumes a crucial position in the regulation of mitochondrial integrity and maintenance. Abnormal mitochondrial quality could result in a spectrum of pathological conditions related to metabolic dysfunction, including metabolic syndrome, cardiovascular ailments, and neoplasms. Recently, there has been a proliferation of research pertaining to the process of mitophagy in the context of MS, and there are various regulatory pathways in MS, including pathways like the ubiquitin‐dependent mechanism and receptor‐mediated mechanisms, among others. Furthermore, studies have uncovered that the process of mitophagy serves a defensive function in the advancement of Metabolic Syndrome, and inhibition of mitophagy exacerbates the advancement of MS. As a result, the regulation of mitophagy holds great promise as a therapeutic approach in the management of Metabolic Syndrome. In this comprehensive analysis, the authors present a synthesis of the diverse regulatory pathways involved in mitophagy in the context of Metabolic Syndrome, as well as its modes of action in metabolic disorders implicated in the development of MS, Including obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM), offering novel avenues for the prophylaxis and therapeutic management of MS.

F I G U R E 1 Relationship between mitophagy and MS. MS refers to a conglomeration of metabolic disturbances that encompass overweight, IR, hypertension and abnormal lipid levels. Promotion of mitophagy occurs through specific receptors on the outer mitochondrial membrane or through ubiquitin molecules attached to proteins on the mitochondrial surface, resulting in the formation of autophagosomes surrounding the mitochondria. A growing number of studies have shown that mitophagy has been linked to a range of metabolic disturbances including obesity, IR, T2DM, NAFLD, atherosclerosis (AS), and heart disease, which are pathologically associated with mitophagy dysfunction and may influence the onset of MetS. Source: Ref [8].
over-consumption of calorie-dense foods and sedentary lifestyles.
These factors result in imbalances in energy intake and expenditure, leading to excess weight gain and accumulation of abdominal fat. This, in turn, increases the risk of insulin resistance and the development of the cluster of health problems associated with metabolic syndrome. 2 In the United States, MS is estimated to affect 34.7% of adults, 3 and with the global spread of Western lifestyles, the incidence of MS is increasing dramatically not only in the United States and Europe, but also in Asian countries such as China, Korea, and India, 4,5 and MS has now become a truly global problem. It is estimated that by 2040 there will be about 2.568 billion people living with MS worldwide. 1 Autophagy is a cellular degradation pathway that is characterized by its dependence on lysosomes and is widely prevalent in eukaryotic cells as a self-protective mechanism to maintain a self-stabilizing intracellular environment. 6 Mitophagy, a form of macroautophagy, is the process the process of autophagy facilitates the selective removal of damaged mitochondria from cells, which are then transported to lysosomes for subsequent degradation, thereby maintaining mitochondrial homeostasis. Mitophagy is widely recognized as a crucial mechanism of mitochondrial quality control (MQC) and involves three main pro-cesses: disruption of the mitochondrial membrane potential, triggering mitochondrial depolarization, and promoting the buildup of mitophagy receptors on the outer mitochondrial membrane (OMM). An increasing body of research has demonstrated a correlation between the cellular process of mitophagy and various metabolic disorders, including obesity, 7 insulin resistance (IR), 8 Type 2 diabetes mellitus (T2DM), 9 non-alcoholic fatty liver disease (NAFLD), 10 atherosclerosis (AS), and heart disease, 11 which are pathologically associated with mitophagy dysfunction and may influence the onset of MS. Therefore, the authors present a comprehensive overview of the underlying mechanisms in the MS and its related metabolic diseases ( Figure 1).

MITOPHAGY PATHWAYS IN MS
Mitophagy can be triggered through a variety of pathways, such as nutritional deficiency (starvation), disruption of the mitochondrial membrane potential, respiratory depression, hypoxia, and ROS accumulation. 12 Presently, there exist two principal regulatory pathways that regulate the process of mitophagy: The first is mitophagy chiefly overseen by PTEN-induced putative kinase 1 (PINK1)/cytoplasmic E3 ubiquitin ligase (Parkin) and non-Parkindependent ubiquitin-dependent mitophagy; The second refers to mitophagy mediated by mitophagy receptors, that is, non-ubiquitindependent mitophagy. 13 These mitophagy receptors are usually mitochondrial proteins containing the microtubule-associated protein It has been well documented that impaired mitochondrial function is associated with MS and that mitochondrial autophagy leads to impaired mitochondrial function and is involved in the development of MS. 8,14

Parkin/PINK1
Mitophagy is mainly regulated by the PINK1/Parkin pathway, PINK1/Parkin-driven mitophagy is the most characteristic pathway and the field of mitophagy is founded on the study of these two proteins. 15  Hoshino and colleagues demonstrate that PINK1/Parkin pathwayderived mitophagy protects pancreatic β-cells and improves glucose intolerance in T2DM patients. 18 Also, Wang and colleagues found that Long non-coding RNA H19 exerts a restraining effect on excessive mitophagy by restricting the expression of Pink1 protein, which alleviates this cardiac abnormality that arises during the condition of obesity. 19 These studies demonstrated that the development of metabolic syndrome (MS) is associated with the PINK1/Parkin pathway-intervened process of mitophagy.

FUNDC1
FUNDC1 is a newly discovered OMM protein that serves as a receptor for hypoxia-induced mitophagy. It possesses a characteristic LIR motif and three TM structural domains near the N-terminal region. 12 Mutations in the LIR motif of FUNDC1 result in the disruption of FUNDC1-LC3 interactions and the induction of mitophagy. The function of FUNDC1 is subject to regulation through reversible phosphorylation and ubiquitination, thereby enabling the detachment of damaged mitochondria and the initiation of mitophagy. 20

Others
Bcl-2-like protein 13 (BCL2L13), which was recognized as BCL2-RAMBO, is another OMM protein that is involved in mitochondrial fission in mammalian cells. Li and colleagues 27 showed the human BCL2L13 protein contains a LIR structural domain, which displays specificity in its binding to three autophagy-related proteins, namely, LC3C, GABARAP, and GABARAP-L1 in cells lacking Atg32, which in turn promotes mitophagy. BCL2L13 is significant in controlling apoptosis, mitochondrial fracture, and promoting mitochondrial autophagy. 28 Ju and colleagues 29 were the first to publish the novel finding that BCL2L13 promotes the differentiation and facilitation process of adipocytes. Subsequently, a study by Fujiwara and colleagues 30

MITOPHAGY IN MS
In general, metabolic diseases such as obesity, IR, T2DM, NAFLD, AS, and heart disease lead to abnormal mitochondrial metabolism, which in turn leads to inadequacy β-oxidation, oxidative stress, and accumulation of toxic lipid antioxidants and mitochondrial dysfunction, and mitochondrial autophagy can treat such metabolic diseases by eliminating this oxidative stress and mitochondrial damage. 34 In addition, mitochondrial autophagy was found to protect the adipose tissue microenvironment by suppressing obesity-induced chronic inflammation, excessive oxidative stress, and ER stress, 35

Mitophagy and obesity
Obesity is a natural consequence of excessive energy intake and sedentary lifestyle, mainly influenced by genetic and environmental factors.
Excessive fat deposition in internal organs produces chronic inflammation, which eventually leads to glucolipid abnormalities, hypertension, diabetes, and other complications associated with IR and MS. 38 It was found that in the muscle of FUNDC1 − / − mice, LC3-mediated mitophagy is defective and ATP is reduced, but protective against highfat-diet (HFD) induced obesity, while also improving systemic insulin sensitivity and glucose tolerance. 39 Lin and colleagues 40 suggest that sesamol may promote the browning of white adipocytes. Recent studies have found that binding of the nuclear receptors (NR1D1 and ULK1) by which adipocytes are induced to undergo mitophagy, thereby alleviating overweight. 41 The above studies demonstrate that increased mitophagy may alleviate obesity and that defects in mitophagy are protective against obesity.

Mitophagy and IR
Typically, IR is considered to be the underlying causative factor not only for the metabolic syndrome but also for its associated NAFLD, obesityrelated T2DM and atherosclerotic cardiovascular disease (ASCVD). 42 Extensive research has shown that mitophagy can improve MQC by increasing ROS production and inhibiting the inflammatory response in adipocytes, thereby inhibiting hepatic IR and steatosis. 8,43 A recent study found that ginsenoside CK could activate mitophagy in skeletal muscle through the DRP1/PINK1 pathway to maintain MQC, thereby reducing IR in diabetic mice. 44 In brief, mitophagy can exert its inhibitory effects in IR by maintaining MQC, promoting oxidative stress and inhibiting inflammatory responses, but there are still few studies on the related molecular mechanisms, and a large number of experiments are needed to verify them.

Mitophagy and T2DM
The metabolic stress triggered by T2DM can lead to pancreatic βcell dysfunction and IR, 45 and likewise, these contribute to MS. It has been found that there are many natural products that regulate mitophagy such as curcumin, caffeine, quercetin, berberine, and vitamins that can improve mitochondrial dysfunction related to T2DM. 45 The correlation of T2DM and ischemia-reperfusion is inextricably linked, and adiponectin was found to attenuate the damage caused by reduced blood flow followed by its restoration, leading to an increase in oxidative stress, inflammation, cell death, and disrupted function of the mitochondria in lung-injured tissues of T2DM mice by activating SIRT1-PINK1 signaling-mediated mitohagy. 46

Mitophagy and NAFLD
NAFLD is the development of steatosis of the liver, whether had inflammation, fibrosis or not, lack of confounding factors such as excessive alcohol intake that may contribute to secondary liver lipid accumulation. Primary harmful index, for example, obesity, T2DM, and dyslipidemia; therefore, it can be considered a hepatic manifestation of the MS. 48 In recent years, a new concept called "metabolic (dysfunction) associated fatty liver, MAFLD" has even emerged to describe the relationship between NAFLD and metabolic dysfunction, emphasizing the simultaneous presence of lipid deposition in liver and abnormal metabolic function. 49 Zhou and colleagues 50

ACKNOWLEDGMENTS
We thank all authors for their outstanding contributions to this paper, especially Dr. Yubo Han, who was responsible for the revision and review of this paper, and Dr. Li Liu, who provided financial support for this paper. National Natural Science Foundation of China, Grant/Award Numbers: 82074346.