Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis

Sustarsic, Elahu G.; Ma, Tao; Lynes, Matthew D.; Larsen, Michael; Karavaeva, Iuliia; Havelund, Jesper Foged; Nielsen, Carsten H.; Jedrychowski, Mark P.; Moreno-Torres, Marta; Lundh, Morten; Plucińska, Kaja; Jespersen, Naja Zenius; Grevengoed, Trisha J.; Kramar, Barbara; Peics, Julia; Hansen, Jakob Bondo; Shamsi, Farnaz; Forss, Isabel; Neess, Ditte; Keipert, Susanne; Wang, Jianing; Stohlmann, Katharina; Brandslund, Ivan; Christensen, Cramer; Jørgensen, Marit E.; Linneberg, Allan; Pedersen, Oluf; Kiebish, Michael A.; Qvortrup, Klaus; Han, Xianlin; Pedersen, Bente Klarlund; Jastroch, Martin; Mandrup, Susanne; Kjær, Andreas; Gygi, Steven P.; Hansen, Torben; Gillum, Matthew P.; Grarup, Niels; Emanuelli, Brice; Nielsen, Søren; Schéele, Camilla; Tseng, Yu–Hua; Færgeman, Nils J.; Gerhart-Hines, Zachary

doi:10.1016/j.cmet.2018.05.003

Cited by 122 publications

(147 citation statements)

References 70 publications

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“…CRLS1 overexpression in cardiac tissue improves the bioenergetics function of isolated mitochondria, potentially by increasing the ability of mitochondria to deal with increased energetic demands (Kiebish et al, 2012). Cardiolipin has been shown to bind directly to UCP1 and increase its stability in the mitochondrial membrane (Lee et al, 2015), and cardiolipin synthesis in brown and beige fat is essential for systemic energy homeostasis (Sustarsic et al, 2018). …”

Section: Discussionmentioning

confidence: 99%

Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism

et al. 2018

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SUMMARY Thermogenic fat expends energy during cold for temperature homeostasis, and its activity regulates nutrient metabolism and insulin sensitivity. We measured cold-activated lipid landscapes in circulation and in adipose tissue by MS/MSALL shotgun lipidomics. We created an interactive online viewer to visualize the changes of specific lipid species in response to cold. In adipose tissue, among the approximately 1,600 lipid species profiled, we identified the biosynthetic pathway of the mitochondrial phospholipid cardiolipin as coordinately activated in brown and beige fat by cold in wild-type and transgenic mice with enhanced browning of white fat. Together, these data provide a comprehensive lipid bio-signature of thermogenic fat activation in circulation and tissue and suggest pathways regulated by cold exposure.

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Section: Discussionmentioning

confidence: 99%

Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism

et al. 2018

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“…Mammalian cells are larger than cells of insects and plants as well as than bacteria. 17 The importance of CL in cell viability in multicellular organisms may depend not only on cell size but also on the function and the environment of cells. The cell size bears a direct relation to the mitochondrial size and number of ATP synthase complexes in a cell.…”

Section: Discussionmentioning

confidence: 99%

“…11 In sharp contrast, CL synthase-deficient mutant of a unicellular eukaryote, Trypanosoma brucei, which has a bacteria-type CL synthase, is lethal. 17 The Crls1-deficient adipose had low levels of CL and attenuated thermogenesis; however, cell death of the adipocytes or developmental defect of the adipose was not described. 17 The Crls1-deficient adipose had low levels of CL and attenuated thermogenesis; however, cell death of the adipocytes or developmental defect of the adipose was not described.…”

Section: Introductionmentioning

confidence: 99%

“…16 Recently, adipose-specific Crls1 cKO mice were reported. 17 The physiologic roles of CL in mammals has been studied particularly using knockdown mice deficient in Taz gene, 18,19 which is the causative gene for Barth syndrome (BTHS) accompanying reduced levels of CL and alteration of CL species. 17 The physiologic roles of CL in mammals has been studied particularly using knockdown mice deficient in Taz gene, 18,19 which is the causative gene for Barth syndrome (BTHS) accompanying reduced levels of CL and alteration of CL species.…”

Section: Introductionmentioning

confidence: 99%

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Cardiolipin is essential for early embryonic viability and mitochondrial integrity of neurons in mammals

et al. 2019

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Cardiolipin (CL) is a hallmark phospholipid of mitochondria and plays a significant role in maintaining the mitochondrial structure and functions. Despite the physiological importance of CL, mutant organisms, yeast, Arabidopsis, C elegans, and Drosophila, which lack CL synthase (Crls1) gene and consequently are deprived of CL, are viable. Here we report conditional Crls1-deficient mice using targeted insertion of loxP sequences flanking the functional domain of CRLS1 enzyme.Homozygous null mutant mice exhibited early embryonic lethality at the peri-implantation stage. We generated neuron-specific Crls1 knockout (cKO) mice by crossing with Camk2α-Cre mice. Neuronal loss and gliosis were gradually manifested in the forebrains, where CL levels were significantly decreased. In the surviving neurons, malformed mitochondria with bubble-like or onion-like inner membrane structures were observed. We showed decreased supercomplex assembly and reduced enzymatic activities of electron transport chain complexes in the forebrain of cKO mice, resulting in affected mitochondrial calcium dynamics, a slower rate of Ca 2+ uptake and a smaller calcium retention capacity. These observations clearly demonstrate indispensable roles of CL as well as of Crls1 gene in mammals.

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“…In agreement with our model, cold-induced browning of WAT, which also increases mitochondrial expansion, reduces TG abundance and leads to elevated levels of free FAs, PC and CL 49 . Moreover, synthesis of CL is essential for mitochondrial biogenesis during cold-exposure 50 . Finally, wholebody deletion of the lipogenic transcription factor Srebf1c abrogates lipogenesis and mitochondrial biogenesis in the WAT of DR fed mice, thus strongly implicating Srebf1-driven lipid synthesis in adipose tissue as a limiting element for mitochondrial dynamics and potentially, essential for improved survival under DR 47 .…”

Section: Discussionmentioning

confidence: 99%

A nutritional memory impairs survival, transcriptional and metabolic response to dietary restriction in old mice

Hahn

Nguyẽ̂n

Tatsuta

et al. 2019

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A nutritional memory impairs survival, transcriptional and metabolic response to dietary restriction in old mice Abstract Dietary restriction (DR) during adulthood can greatly extend lifespan and improve metabolic health in diverse species. However, whether DR in mammals is still effective when applied for the first time at old age remains elusive. Here, we conducted a late-life DR switch experiment employing 800 mice, by switching old animals from ad libitum (AL) to DR and vice versa. Strikingly, the switch from DR-to-AL acutely increased mortality, while the switch from AL-to-DR caused only a weak and gradual increase in survival, highlighting a memory of earlier nutrition. A significant association between fat preservation and survival response pointed to the white adipose tissue (WAT) as a potential memory source. Consistently, post-switch RNA-seq profiling in liver and WAT demonstrated that the transcriptional and metabolic program of chronic DR remained largely refractory to the AL-to-DR switch specifically in adipose tissue. Integration of lipidomics confirmed impaired membrane lipogenesis and limited mitochondrial copy number increase under late-life DR as functional consequences of this memory effect. Together, our results provide evidence for a nutritional memory as a limiting factor for DR-induced longevity and metabolic remodeling of WAT in mammals.

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Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis

Cited by 122 publications

References 70 publications

Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism

Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism

Cardiolipin is essential for early embryonic viability and mitochondrial integrity of neurons in mammals

A nutritional memory impairs survival, transcriptional and metabolic response to dietary restriction in old mice

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