Let's burn whatever you have: mitofusin 2 metabolically re‐wires brown adipose tissue

Scheideler, Marcel; Herzig, Stephan

doi:10.15252/embr.201744341

Cited by 8 publications

(4 citation statements)

References 10 publications

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“…PLIN5 reportedly regulates mitochondrial recruitment to LD, thereby regulating mitochondrial metabolism ( 8 , 29 , 30 ). On the other hand, MFN2 not only promotes mitochondrial fusion and boosts mitochondrial metabolism ( 31 , 32 ), but also binds to PLIN1 to facilitate the LD-mitochondria interaction in adipose tissue ( 17 , 33 ). Due to their importance, we measured their relative abundance in our experimental model through Western blot analysis ( Figure 3A ).…”

Section: Resultsmentioning

confidence: 99%

Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in the Hepatic Cell Line HepG2

et al. 2021

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Fatty acid overload, either of the saturated palmitic acid (PA) or the unsaturated oleic acid (OA), causes triglyceride accumulation into specialized organelles termed lipid droplets (LD). However, only PA overload leads to liver damage mediated by mitochondrial dysfunction. Whether these divergent outcomes stem from differential effects of PA and OA on LD and mitochondria joint dynamics remains to be uncovered. Here, we contrast how both fatty acids impact the morphology and interaction between both organelles and mitochondrial bioenergetics in HepG2 cells. Using confocal microscopy, we showed that short-term (2–24 h) OA overload promotes more and bigger LD accumulation than PA. Oxygen polarography indicated that both treatments stimulated mitochondrial respiration; however, OA favored an overall build-up of the mitochondrial potential, and PA evoked mitochondrial fragmentation, concomitant with an ATP-oriented metabolism. Even though PA-induced a lesser increase in LD-mitochondria proximity than OA, those LD associated with highly active mitochondria suggest that they interact mainly to fuel fatty acid oxidation and ATP synthesis (that is, metabolically “active” LD). On the contrary, OA overload seemingly stimulated LD-mitochondria interaction mainly for LD growth (thus metabolically “passive” LDs). In sum, these differences point out that OA readily accumulates in LD, likely reducing their toxicity, while PA preferably stimulates mitochondrial oxidative metabolism, which may contribute to liver damage progression.

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Section: Resultsmentioning

confidence: 99%

Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in the Hepatic Cell Line HepG2

et al. 2021

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“…Also during the fast-to-fed transition, mice lacking Mfn1 in POMC neurons exhibit defective mitochondrial architecture and flexibility, which results in defective insulin secretion and abnormal glucose homeostasis by pancreatic β cells (56). Mfn2, but not Mfn1, deletion in brown adipose tissue (BAT) remodels the mitochondrial dysfunction, leading to an increase in insulin sensitivity and resistance to obesity (51, 52, 77). These observations have implicated a crucial role of mitofusins in the control of mitochondrial energy metabolism and insulin resistance.…”

Section: Imbalanced Mitochondrial Metabolism Results In Obesity and Dmentioning

confidence: 99%

Dysregulated Mitochondrial Dynamics and Metabolism in Obesity, Diabetes, and Cancer

Dai¹,

Jiang

2019

Front. Endocrinol.

138

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Metabolism describes the life-sustaining chemical reactions in organisms that provide both energy and building blocks for cellular survival and proliferation. Dysregulated metabolism leads to many life-threatening diseases including obesity, diabetes, and cancer. Mitochondria, subcellular organelles, contain the central energy-producing metabolic pathway, the tricarboxylic acid (TCA) cycle. Also, mitochondria exist in a dynamic network orchestrated by extracellular nutrient levels and intracellular energy needs. Upon stimulation, mitochondria undergo consistent interchange through fusion (small to big) and fission (big to small) processes. Mitochondrial fusion is primarily controlled by three GTPases, mitofusin 1 (Mfn1), Mfn2, and optic atrophy 1 (Opa1), while mitochondrial fission is primarily regulated by GTPase dynamin-related protein 1 (Drp1). Dysregulated activity of these GTPases results in disrupted mitochondrial dynamics and cellular metabolism. This review will update the metabolic roles of these GTPases in obesity, diabetes, and cancer.

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“… 31 Moreover, in adipose tissue the association between mitochondria and lipid droplets is important for both lipid storage and consumption, 109 , 110 while adipocyte specific knockout of MFN2 leads to obesity in mice. 34 , 111 , 112 Finally, the R707W MFN2 variant, which causes CMT2A when present heterozygously, also causes lipomatosis when present homozygously. 51 , 52 Thus, it is clear that the roles of MFN2 in maintaining lipid homeostasis are important, though the exact molecular mechanisms remain undefined.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a novel variant in the HR1 domain of MFN2 in a patient with ataxia, optic atrophy and sensorineural hearing loss

et al. 2022

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Background: Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Method: Several MFN2-mediated functions were characterized in fibroblast cells from a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy, who harbours a novel homozygous MFN2 variant, D414V, which is found in a region of the HR1 domain of MFN2 where few pathogenic variants occur. Results: We found evidence for impairment of several MFN2-mediated functions. Consistent with reduced mitochondrial fusion, patient fibroblasts exhibited more fragmented mitochondrial networks and had reduced mtDNA copy number. Additionally, patient fibroblasts had reduced oxygen consumption, fewer mitochondrial-ER contacts, and altered lipid droplets that displayed an unusual perinuclear distribution. Conclusion: Overall, this work characterizes D414V as a novel variant in MFN2 and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.

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Let's burn whatever you have: mitofusin 2 metabolically re‐wires brown adipose tissue

Cited by 8 publications

References 10 publications

Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in the Hepatic Cell Line HepG2

Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in the Hepatic Cell Line HepG2

Dysregulated Mitochondrial Dynamics and Metabolism in Obesity, Diabetes, and Cancer

Characterization of a novel variant in the HR1 domain of MFN2 in a patient with ataxia, optic atrophy and sensorineural hearing loss

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