Mitochondrial glycerol 3-phosphate dehydrogenase deficiency exacerbates lipotoxic cardiomyopathy.

Metabolic diseases such as obesity and diabetes induce lipotoxic cardiomyopathy, which is characterized by myocardial lipid accumulation, dysfunction, hypertrophy, fibrosis and mitochondrial dysfunction. Here, we identify that mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is a pivotal regulator of cardiac fatty acid metabolism and function in the setting of lipotoxic cardiomyopathy. Cardiomyocyte-specific deletion of mGPDH promotes high-fat diet induced cardiac dysfunction, pathological hypertrophy, myocardial fibrosis, and lipid accumulation. Mechanically, mGPDH deficiency inhibits the expression of desuccinylase SIRT5, and in turn, the hypersuccinylates majority of enzymes in the fatty acid oxidation (FAO) cycle and promotes the degradation of these enzymes. Moreover, manipulating SIRT5 abolishes the effects of mGPDH ablation or overexpression on cardiac function. Finally, restoration of mGPDH improves lipid accumulation and cardiomyopathy in both diet-induced and genetic obese mouse models. Thus, our study indicates that targeting mGPDH could be a promising strategy for lipotoxic cardiomyopathy in the context of obesity and diabetes.

Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism.

Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte-specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α  (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36-mediated fatty acid uptake of podocytes via upregulating LXRα in an m6 A-dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases.

Serum Annexin A2 concentrations are increased in patients with diabetic cardiomyopathy and are linked to cardiac dysfunctions.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is defined as the existence of abnormal myocardial structure and functions in the absence of other cardiac diseases, such as coronary artery disease, hypertension, and significant valvular disease, in individuals with diabetes. Although abundant epidemic evidence demonstrates that diabetes is independently associated with the risk of developing heart failure, DbCM is not normally diagnosed in clinical practices due to its exclusive diagnosis, and no diagnostic biomarker was applied in a clinical test. METHODS: To detect the concentrations of serum Annexin A2 in non-diabetic subjects, type 2 diabetic (T2DM) patients with or without DbCM, and analyzed its relationship to parameters of cardiac functions, glucose, lipid metabolism, and renal functions. 266 eligible participants were included and were divided into 3 groups including non-diabetic subjects (NGR), T2DM patients without DbCM (T2DM group), and the DbCM group. Echocardiography, coronary computed tomography angiography, electrocardiogram, blood pressure, thyroid function, and clinical and other biochemical parameters were measured in all participants. RESULTS: Serum Annexin A2 concentrations were higher in DbCM (P < 0.05) and T2DM (P < 0.05) groups compared with the NGR group, especially in DbCM patients. Correlation analysis showed that serum Annexin A2 levels were negatively associated with left ventricular (LV) ejection fraction (EF), LV fractional shortening (FS), the ratio of early (E-wave) and late (A-wave) LV diastolic filling velocities (E/A ratio), and estimated glomerular filtration rate (eGFR), and were positively correlated with age, blood urea nitrogen (BUN) and creatinine (Cr) (all P < 0.05). Multiple logistical regression analyses revealed that serum in both the second and the third tertiles of Annexin A2 concentration were significantly associated with DbCM. E/A ratio is the independent factor for Annexin A2 concentration when adjusted for LV FS%, BUN, and Cr. CONCLUSIONS: Circulating Annexin A2 concentrations might be induced in DbCM patients and were negatively associated with cardiac systolic and diastolic functions, which suggested it might be a predictor of early diagnosis in DbCM and might be a potential therapeutic target for DbCM.

PSA controls hepatic lipid metabolism by regulating the NRF2 signaling pathway.

The activity of proteinase is reported to correlate with the development and progression of nonalcoholic fatty liver disease (NAFLD). Puromycin-sensitive aminopeptidase (PSA/NPEPPS) is an integral nontransmembrane enzyme that functions to catalyze the cleavage of amino acids near the N-terminus of polypeptides. A previous study suggested that this enzyme acts as a regulator of neuropeptide activity; however, the metabolic function of this enzyme in the liver has not been explored. Here, we identified the novel role of PSA in hepatic lipid metabolism. Specifically, PSA expression was lower in fatty livers from NAFLD patients and mice (HFD, ob/ob, and db/db). PSA knockdown in cultured hepatocytes exacerbated diet-induced triglyceride accumulation through enhanced lipogenesis and attenuated fatty acid ß-oxidation. Moreover, PSA mediated activation of the master regulator of antioxidant response, nuclear factor erythroid 2-related factor 2 (NRF2), by stabilizing NRF2 protein expression, which further induced downstream antioxidant enzymes to protect the liver from oxidative stress and lipid overload. Accordingly, liver-specific PSA overexpression attenuated hepatic lipid accumulation and steatosis in ob/ob mice. Furthermore, in human liver tissue samples, decreased PSA expression correlated with the progression of NAFLD. Overall, our findings suggest that PSA is a pivotal regulator of hepatic lipid metabolism and its antioxidant function occurs by suppressing NRF2 ubiquitination. Moreover, PSA may be a potential biomarker and therapeutic target for treating NAFLD.

mGPDH Deficiency leads to melanoma metastasis via induced NRF2.

Oxidative stress critically influences carcinogenesis and the progression of melanoma, and aggressive malignant melanoma activity is due to its high metastatic ability. Some findings in several cancer cell lines have indicated that mGPDH, a component of the mitochondrial respiratory chain, also modulates oxidative stress. However, the role of mGPDH in melanoma remains elusive. Here, we report that the mGPDH protein level is decreased in human skin melanoma compared to normal skin and decreased in metastatic melanoma compared to primary melanoma. Our in vivo and in vitro experiments indicated that mGPDH depletion accelerated melanoma migration and invasion without affecting proliferation or apoptosis. Mechanistically, we found elevated NRF2 protein levels in human skin melanoma and mGPDH-knockout (ko) metastatic xenografts in the lungs of nude mice. Moreover, in A375 melanoma cells, the loss of mGPDH-induced NRF2 expression but did not affect NRF2 protein degradation. Additionally, melanoma metastasis induced by the loss of mGPDH was rescued by the further down-regulation of NRF2 in vivo and in vitro. Consistently, mGPDH overexpression (oe) depressed NRF2 expression and attenuated the malignant properties of melanoma cells. In conclusion, our findings suggest that mGPDH suppresses melanoma metastasis by inhibiting NRF2 and downstream oxidative signals, highlighting the therapeutic potential of mGPDH for melanoma treatment.

Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Exacerbates Podocyte Injury and the Progression of Diabetic Kidney Disease.

Mitochondrial function is essential for bioenergetics, metabolism, and signaling and is compromised in diseases such as proteinuric kidney diseases, contributing to the global burden of kidney failure, cardiovascular morbidity, and death. The key cell type that prevents proteinuria is the terminally differentiated glomerular podocyte. In this study, we characterized the importance of mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH), located on the inner mitochondrial membrane, in regulating podocyte function and glomerular disease. Specifically, podocyte-dominated mGPDH expression was downregulated in the glomeruli of patients and mice with diabetic kidney disease and adriamycin nephropathy. Podocyte-specific depletion of mGPDH in mice exacerbated diabetes- or adriamycin-induced proteinuria, podocyte injury, and glomerular pathology. RNA sequencing revealed that mGPDH regulated the receptor for the advanced glycation end product (RAGE) signaling pathway, and inhibition of RAGE or its ligand, S100A10, protected against the impaired mitochondrial bioenergetics and increased reactive oxygen species generation caused by mGPDH knockdown in cultured podocytes. Moreover, RAGE deletion in podocytes attenuated nephropathy progression in mGPDH-deficient diabetic mice. Rescue of podocyte mGPDH expression in mice with established glomerular injury significantly improved their renal function. In summary, our study proposes that activation of mGPDH induces mitochondrial biogenesis and reinforces mitochondrial function, which may provide a potential therapeutic target for preventing podocyte injury and proteinuria in diabetic kidney disease.

Dedicator of Cytokinesis 5 Regulates Keratinocyte Function and Promotes Diabetic Wound Healing.

Cutaneous wound healing is a fundamental biologic and coordinated process, and failure to maintain this process contributes to the dysfunction of tissue homeostasis, increasing the global burden of diabetic foot ulcerations. However, the factors that mediate this process are not fully understood. Here, we identify the pivotal role of dedicator of cytokinesis 5 (Dock5) in keratinocyte functions contributing to the process of skin wound healing. Specifically, Dock5 is highly upregulated during the proliferative phase of wound repair and is predominantly expressed in epidermal keratinocytes. It regulates keratinocyte adhesion, migration, and proliferation and influences the functions of extracellular matrix (ECM) deposition by facilitating the ubiquitination of transcription factor ZEB1 to activate laminin-332/integrin signaling. Genetic ablation of Dock5 in mice leads to attenuated reepithelialization and granulation tissue formation, and Dock5 overexpression-improved skin repair can be abrogated by LAMA3 knockdown. Importantly, Dock5 expression in the skin edge is reduced in patients and animal models of diabetes, further suggesting a direct correlation between its abundance and healing capability. The rescue of Dock5 expression in diabetic mice causes a significant improvement in reepithelialization, collagen deposition, ECM production, and granulation. Our study provides a potential therapeutic target for wound healing impairment during diabetes.

The potential effects of clinical antidiabetic agents on SARS-CoV-2.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is currently posing significant threats to public health worldwide. It is notable that a substantial proportion of patients with sever COVID-19 have coexisting diabetic conditions, indicating the progression and outcome of COVID-19 may relate to diabetes. However, it is still unclear whether diabetic treatment principles can be used for the treatment of COVID-19. METHODS: We conducted a computational approach to screen all commonly used clinical oral hypoglycemic drugs to identify the potential inhibitors for the main protease (Mpro ) of SARS-CoV-2, which is one of the key drug targets for anti-COVID-19 drug discovery. RESULTS: Six antidiabetic drugs with docking scores higher than 8.0 (cutoff value), including repaglinide, canagliflozin, glipizide, gliquidone, glimepiride, and linagliptin, were predicted as the promising inhibitors of Mpro . Interestingly, repaglinide, one of the six antidiabetic drugs with the highest docking score for Mpro , was similar to a previously predicted active molecule nelfinavir, which is a potential anti-HIV and anti-COVID-19 drug. Moreover, we found repaglinide shared similar docking pose and pharmacophores with a reported ligand (N3 inhibitor) and nelfinavir, demonstrating that repaglinide would interact with Mpro in a similar way. CONCLUSION: These results indicated that these six antidiabetic drugs may have an extra effect on the treatment of COVID-19, although further studies are necessary to confirm these findings.

Deficiency of Mitochondrial Glycerol 3-Phosphate Dehydrogenase Contributes to Hepatic Steatosis.

Mitochondrial glycerol 3-phosphate dehydrogenase (mGPDH) is an integral component of the respiratory chain, and recent studies have suggested that it plays an important role in hepatic glucose homeostasis. However, its function in hepatic lipid metabolism is unclear. Here, we identified a role for mGPDH in nonalcoholic fatty liver disease (NAFLD). Specifically, mGPDH expression and activity were lower in fatty livers from patients and mice with NAFLD (ob/ob, high-fat diet [HFD] and db/db). Liver-specific depletion of mGPDH in mice or mGPDH knockdown in cultured hepatocytes exacerbated diet-induced triglyceride accumulation and steatosis through enhanced lipogenesis. RNA-sequencing revealed that mGPDH regulated endoplasmic reticulum (ER)-related proteins and processes. mGPDH deletion exacerbated tunicamycin (ER stress inducer)-induced hepatic steatosis, whereas tauroursodeoxycholic acid (ER stress inhibitor) rescued mGPDH depletion-induced steatosis on an HFD. Moreover, ER stress induced by mGPDH depletion could be abrogated by the intracellular Ca2+ chelator 1,2-bis (2-aminophenoxy) ethane N,N,N´,N´-tetraacetic acid acetoxymethyl ester, mitochondrial permeability transition pore (mPTP) inhibitor cyclosporine A, or cyclophilin-D (Cyp-D) knockdown. mGPDH promoting Cyp-D ubiquitination was also observed. Finally, liver-specific mGPDH overexpression attenuated hepatic steatosis in ob/ob and HFD mice. Conclusion: mGPDH is a pivotal regulator of hepatic lipid metabolism. Its deficiency induces ER stress by suppressing Cyp-D ubiquitination, a key regulator of the mitochondrial Ca2+ conductance channel mPTP, and results in hepatic steatosis. mGPDH may be a potential therapeutic target for the treatment of NAFLD.

Mitochondrial glycerol 3-phosphate dehydrogenase promotes skeletal muscle regeneration.

While adult mammalian skeletal muscle is stable due to its post-mitotic nature, muscle regeneration is still essential throughout life for maintaining functional fitness. During certain diseases, such as the modern pandemics of obesity and diabetes, the regeneration process becomes impaired, which leads to the loss of muscle function and contributes to the global burden of these diseases. However, the underlying mechanisms of the impairment are not well defined. Here, we identify mGPDH as a critical regulator of skeletal muscle regeneration. Specifically, it regulates myogenic markers and myoblast differentiation by controlling mitochondrial biogenesis via CaMKKß/AMPK. mGPDH-/- attenuated skeletal muscle regeneration in vitro and in vivo, while mGPDH overexpression ameliorated dystrophic pathology in mdx mice. Moreover, in patients and animal models of obesity and diabetes, mGPDH expression in skeletal muscle was reduced, further suggesting a direct correlation between its abundance and muscular regeneration capability. Rescuing mGPDH expression in obese and diabetic mice led to a significant improvement in their muscle regeneration. Our study provides a potential therapeutic target for skeletal muscle regeneration impairment during obesity and diabetes.

DPP-4 Inhibitors Improve Diabetic Wound Healing via Direct and Indirect Promotion of Epithelial-Mesenchymal Transition and Reduction of Scarring.

Patients with diabetes often experience multiple disease complications. Hypoglycemic agents can have both positive and negative effects on diabetic complications, which should be carefully assessed when personalized treatment strategies are developed. In this study we report that dipeptidyl peptidase 4 inhibitors (DPP-4is), a group of widely used antihyperglycemic agents, can improve diabetic wound healing, independent of their beneficial effects on glycemic control. In particular, DPP-4is promoted the migration and epithelial-mesenchymal transition of keratinocytes, directly and indirectly, by inducing stromal cell-derived factor 1α production of fibroblasts in vitro and in diabetic mice. In addition, DPP-4is attenuated collagen synthesis and deposition, which may diminish scar formation. Furthermore, the results of a randomized clinical trial (NCT02742233) involving 67 patients with type 2 diabetes supported the role of DPP-4i treatment in diabetic wound healing. Our findings support the application of DPP-4i as a preferred option for treating ulcers in patients with diabetes.

NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis.

Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that antidiabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic α-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor E2-related factor 2 (NRF2)-mediated antioxidant response through inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.