Parkin‐mediated mitophagy is downregulated in browning of white adipose tissue

Taylor, David J.; Gottlieb, Roberta A.

doi:10.1002/oby.21786

Cited by 53 publications

(46 citation statements)

References 40 publications

(38 reference statements)

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“…In conclusion, these data suggest that enhanced mitophagy in cold-challenged BAT is mediated by mitochondrial UCP-1 activation and may be dependent on the mitochondrial stress sensor PINK1. It has been reported in other adipose depots, i.e., beige adipose, mitochondrial stress sensor Parkin were differentially regulated in responded to CL stimulation 56 . The role of UCP-1 in beige fat mitophagy is unknown and will be a subject of our future studies.…”

Section: Resultsmentioning

confidence: 84%

Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge

Lü

Fujioka

Joshi

et al. 2018

Sci Rep

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Brown adipose tissue (BAT) is a specialized thermogenic organ in mammals. The ability of BAT mitochondria to generate heat in response to cold-challenge to maintain core body temperature is essential for organismal survival. While cold activated BAT mitochondrial biogenesis is recognized as critical for thermogenic adaptation, the contribution of mitochondrial quality control to this process remains unclear. Here, we show mitophagy is required for brown adipocyte mitochondrial homeostasis during thermogenic adaptation. Mitophagy is significantly increased in BAT from cold-challenged mice (4 °C) and in β-agonist treated brown adipocytes. Blockade of mitophagy compromises brown adipocytes mitochondrial oxidative phosphorylation (OX-PHOS) capacity, as well as BAT mitochondrial integrity. Mechanistically, cold-challenge induction of BAT mitophagy is UCP1-dependent. Furthermore, our results indicate that mitophagy coordinates with mitochondrial biogenesis, maintaining activated BAT mitochondrial homeostasis. Collectively, our in vivo and in vitro findings identify mitophagy as critical for brown adipocyte mitochondrial homeostasis during cold adaptation.

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Section: Resultsmentioning

confidence: 84%

Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge

Lü

Fujioka

Joshi

et al. 2018

Sci Rep

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“…As shown in Fig. 5, we added oligomycin, FCCP, and antimycin/rotenone in series to alter mitochondrial function, as previously described (42,56). This assay, known as the mitochondrial stress test, allowed us to determine mitochondria-related basal respiration, ATP production, proton leak, maximum respiration, spare respiratory capacity, and nonmitochondrial respiration, as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Mitochondrial respirometry. Cellular metabolism was measured using a Seahorse Bioscience XFe24 extracellular flux analyzer, as previously described (42,56). After 5 days in culture, cell media was replaced with XF Assay Medium (Seahorse Bioscience) supplemented with 10 mM glucose, 2 M L-glutamine, and 1 mM sodium pyruvate (pH 7.4), and the plate was incubated for 1 h in a 37°C, non-CO2 incubator.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial function in engineered cardiac tissues is regulated by extracellular matrix elasticity and tissue alignment

Lyra-Leite

Andres

Petersen

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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Mitochondria in cardiac myocytes are critical for generating ATP to meet the high metabolic demands associated with sarcomere shortening. Distinct remodeling of mitochondrial structure and function occur in cardiac myocytes in both developmental and pathological settings. However, the factors that underlie these changes are poorly understood. Because remodeling of tissue architecture and extracellular matrix (ECM) elasticity are also hallmarks of ventricular development and disease, we hypothesize that these environmental factors regulate mitochondrial function in cardiac myocytes. To test this, we developed a new procedure to transfer tunable polydimethylsiloxane disks microcontact-printed with fibronectin into cell culture microplates. We cultured Sprague-Dawley neonatal rat ventricular myocytes within the wells, which consistently formed tissues following the printed fibronectin, and measured oxygen consumption rate using a Seahorse extracellular flux analyzer. Our data indicate that parameters associated with baseline metabolism are predominantly regulated by ECM elasticity, whereas the ability of tissues to adapt to metabolic stress is regulated by both ECM elasticity and tissue alignment. Furthermore, bioenergetic health index, which reflects both the positive and negative aspects of oxygen consumption, was highest in aligned tissues on the most rigid substrate, suggesting that overall mitochondrial function is regulated by both ECM elasticity and tissue alignment. Our results demonstrate that mitochondrial function is regulated by both ECM elasticity and myofibril architecture in cardiac myocytes. This provides novel insight into how extracellular cues impact mitochondrial function in the context of cardiac development and disease. A new methodology has been developed to measure O consumption rates in engineered cardiac tissues with independent control over tissue alignment and matrix elasticity. This led to the findings that matrix elasticity regulates basal mitochondrial function, whereas both matrix elasticity and tissue alignment regulate mitochondrial stress responses.

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“…Expression of parkin and its upstream activating kinase PINK1 increases during adipocyte differentiation and is also increased in white adipose tissue of mice fed an HFD relative to normal chow-fed controls (38,39). This suggests a role of mitophagy during the mitochondrial remodeling that occurs in WAT of obese mice (39).…”

Section: Discussionmentioning

confidence: 96%

The E3 ubiquitin ligase parkin is dispensable for metabolic homeostasis in murine pancreatic β cells and adipocytes

Corsa

Pearson

Renberg

et al. 2019

Journal of Biological Chemistry

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The E3 ubiquitin ligase parkin is a critical regulator of mitophagy and has been identified as a susceptibility gene for type 2 diabetes (T2D). However, its role in metabolically active tissues that precipitate T2D development is unknown. Specifically, pancreatic ␤ cells and adipocytes both rely heavily on mitochondrial function in the regulation of optimal glycemic control to prevent T2D, but parkin's role in preserving quality control of ␤ cell or adipocyte mitochondria is unclear. Although parkin has been reported previously to control mitophagy, here we show that, surprisingly, parkin is dispensable for glucose homeostasis in both ␤ cells and adipocytes during diet-induced insulin resistance in mice. We observed that insulin secretion, ␤ cell formation, and islet architecture were preserved in parkin-deficient ␤ cells and islets, suggesting that parkin is not necessary for control of ␤ cell function and islet compensation for diet-induced obesity. Although transient parkin deficiency mildly impaired mitochondrial turnover in ␤ cell lines, parkin deletion in primary ␤ cells yielded no deficits in mitochondrial clearance. In adipocyte-specific deletion models, lipid uptake and ␤-oxidation were increased in cultured cells, whereas adipose tissue morphology, glucose homeostasis, and beige-to-white adipocyte transition were unaffected in vivo. In key metabolic tissues where mitochondrial dysfunction has been implicated in T2D development, our experiments unexpectedly revealed that parkin is not an essential regulator of glucose tolerance, whole-body energy metabolism, or mitochondrial quality control. These findings highlight that parkin-independent processes maintain ␤ cell and adipocyte mitochondrial quality control in diet-induced obesity.

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Parkin‐mediated mitophagy is downregulated in browning of white adipose tissue

Cited by 53 publications

References 40 publications

Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge

Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge

Mitochondrial function in engineered cardiac tissues is regulated by extracellular matrix elasticity and tissue alignment

The E3 ubiquitin ligase parkin is dispensable for metabolic homeostasis in murine pancreatic β cells and adipocytes

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