The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites

Bean, Camilla; Audano, Matteo; Varanita, Tatiana; Favaretto, Francesca; Medaglia, Marta; Gerdol, Marco; Pernas, Lena; Stasi, Fabio; Giacomello, Marta; Herkenne, Stéphanie; Muniandy, Maheswany; Heinonen, Sini; Cazaly, Emma; Ollikainen, Miina; Milan, Gabriella; Pallavicini, Alberto; Pietiläinen, Kirsi H.; Vettor, Roberto; Mitro, Nico; Scorrano, Luca

doi:10.1038/s42255-021-00497-2

Cited by 61 publications

(29 citation statements)

References 68 publications

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“…S3G), the rate-limiting enzyme of the urea cycle, suggesting a possible upregulation of this pathway. The role of wrappER-mitochondria contacts on hepatic nitrogen metabolism remains to be addressed, but this aspect is of noteworthy because the transition from NAFLD to NASH also involves a loss of control of ammonia detoxification by the urea cycle [50][51][52].…”

Section: Discussionmentioning

confidence: 99%

Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis

et al. 2022

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Background In mouse liver hepatocytes, nearly half of the surface area of every mitochondrion is covered by wrappER, a wrapping-type of ER that is rich in fatty acids and synthesizes lipoproteins (VLDL) (Anastasia et al. in Cell Rep 34:108873, 2021; Hurtley in Science (80- ) 372:142–143, 2021; Ilacqua et al. in J Cell Sci 135:1–11, 2021). A disruption of the ultrastructure of the wrappER-mitochondria contact results in altered fatty acid flux, leading to hepatic dyslipidemia (Anastasia et al. 2021). The molecular mechanism that regulates the extent of wrappER-mitochondria contacts is unknown. Methods We evaluated the expression level of the mitochondrial protein Synj2bp in the liver of normal and obese (ob/ob) mice. In addition, we silenced its expression in the liver using an AAV8 vector. We coupled quantitative EM morphometric analysis to proteomics and lipid analyses on these livers. Results The expression level of Synj2bp in the liver positively correlates with the extent of wrappER-mitochondria contacts. A 50% reduction in wrappER-mitochondria contacts causes hepatic dyslipidemia, characterized by a gross accumulation of lipid droplets in the liver, an increased hepatic secretion of VLDL and triglycerides, a curtailed ApoE expression, and an increased capacity of mitochondrial fatty acid respiration. Conclusion Synj2bp regulates the extent of wrappER-mitochondria contacts in the liver, thus contributing to the control of hepatic lipid flux.

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Section: Discussionmentioning

confidence: 99%

Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis

et al. 2022

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“…OPA1, a mitochondrial fusion protein, is found in the inner mitochondrial membrane. [ 46 ] Western blot (Figure 4a,b) and immunofluorescence (Figure S5, Supporting Information) showed that HG inhibited OPA1 expressions, which were alleviated by PBNs‐loaded MN patches. These results indicate that HG perturbs mitochondrial functions, inhibits antioxidant activities, and aggravates cell apoptosis.…”

Section: Resultsmentioning

confidence: 99%

Multifunctional Silk Fibroin Methacryloyl Microneedle for Diabetic Wound Healing

Guan

Zhang

Jiang

et al. 2022

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of diabetes mellitus. Globally, these wounds are important causes of disability and mortality. [2] Diabetic wounds that fail to heal are largely caused by oxidative stress. [3] Overproduction of reactive oxygen species (ROS) and inadequate antioxidant protection results in excess oxidative stress, leading to cell apoptosis and suppressed cell proliferation as well as differentiation at diabetic wound sites. [4] In high glucose (HG) conditions, glucotoxicity disrupts angiogenesis, thereby limiting the transport and delivery of nutrients and oxygen in diabetic wounds. [5] Diabetic skin wounds are more susceptible to bacterial infections, causing belated healing and life-threatening outcomes. [6,7] Bacterial infections are also involved in oxidative stress induction. [8] Excess oxidative stress levels suppress growth factor-mediated signaling pathways, resulting in dysregulated angiogenesis. Oxidative stress, angiogenesis, and bacterial infections have been reported to jointly cause diabetic wound healing disorders. [9] The existing therapies include drugs or application of bio-activators, hyperbaric oxygen therapy, and stem cell therapy. [10][11][12] However, these therapies are expensive, single-functional, immature, and cumbersome to operate in many cases. [13,14] The limited efficacies create an urgent need for the development of novel treatment modalities.Microneedle (MN) patches are emerging minimally-invasive local delivery systems that have the ability to overcome the dosing inefficiency of systemic delivery. And the new-generation MN, such as bioinspired or stimuli-responsive MN, exhibits more individualized, more efficient, and more convenient. [15,16] These patches have been applied for the treatment of various diseases, including skin wounds. [17,18] However, the current MN patches cannot act on multiple targets of diabetes wound pathogenesis. [19] We developed a multifunctional MN patch with the ability to simultaneously target oxidative stress, angiogenesis, and bacterial infections in diabetic wounds. A silk fibroin methacryloyl hydrogel was selected as the base material for multifunctional MN patches. Silk fibroin methacryloyl was formed from silk fibroin, a physiologically inactive protein derived from Bombyx mori silkworm cocoon, modified with glycidyl-methacrylate groups to supply a cross-linkage site essential for photopolymerization. Silk fibroin methacryloyl has excellent biocompatibility, biodegradability, stable mechanical Diabetic wound is one of the common complications in diabetic patients, which exhibits chronic, hard-to-heal characteristics. The healing process of wounds is impaired by several factors, including excessive oxidative stress, blocked angiogenesis, and bacterial infection. The therapeutic effects of traditional microneedle patches remain not satisfactory, due to their difficulty simultaneously targeting multiple targets to treat diabetic wounds. As such, there is an urgent need to develop a multifunctional microneedle (MN) patch for promoting the healing of diabetic wounds. ...

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“…OPA1 promotes autonomous browning of adipocytes, and brown adipose tissue reduces obesity through energy conversion. By contrast, reduced OPA1 expression in overnutrition impairs adipocyte plasticity, thus exacerbating the obesity phenotype [ 119 ].…”

Section: Mutual Regulation Between Mitochondrial Dysfunction and Meta...mentioning

confidence: 99%

Mitochondrial Stress in Metabolic Inflammation: Modest Benefits and Full Losses

Yuan

Zeng

Yang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Energy intake and metabolic balance are the pillars of health preservation. Overnutrition causes nonspecific, persistently low inflammatory state known as metabolic inflammation. This condition contributes to the pathophysiology of various metabolic disorders, such as atherosclerosis, obesity, diabetes mellitus, and metabolic syndrome. The mitochondria maintain the balance of energy metabolism. Excessive energy stress can lead to mitochondrial dysfunction, which promotes metabolic inflammation. The inflammatory environment further impairs mitochondrial function. Accordingly, excellent organism design keeps the body metabolically healthy in the context of mitochondrial dysfunction, and moderate mitochondrial stress can have a beneficial effect. This review summarises the research progress on the multifaceted characterisation of mitochondrial dysfunction and its role in metabolic inflammation.

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The mitochondrial protein Opa1 promotes adipocyte browning that is dependent on urea cycle metabolites

Cited by 61 publications

References 68 publications

Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis

Expression of Synj2bp in mouse liver regulates the extent of wrappER-mitochondria contact to maintain hepatic lipid homeostasis

Multifunctional Silk Fibroin Methacryloyl Microneedle for Diabetic Wound Healing

Mitochondrial Stress in Metabolic Inflammation: Modest Benefits and Full Losses

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