Role of Subcellular Molecular Architecture in Metabolic Program

Role of Subcellular Molecular Architecture in Metabolic Program

We have recently discovered that dynamic regulation of subcellular compartmentalization is a critically important dimension of metabolic activity and output of cells.  We have been interested in this critical and fundamental question and how it applies to metabolic responses under physiological fluctuations of supply and demand as well as during metabolic pathologies associated with obesity and aging.  The initial leads to this program emerged from studies in liver tissue in obese animals, where we observed a marked enrichment of ER-Mitochondria interactions (MAMs).  This unusual form of interaction results in abnormal calcium fluxes, mitochondrial dysfunction, oxidative stress, and metabolic impairments. These studies also suggested the possibility of dynamic regulation of the structures in healthy cells but the loss of this plasticity in the context of metabolic disease.  More recently, we completed a critical study using advanced imaging technologies in large liver tissue volumes, we generated the highest resolution of subcellular structures in a native tissue environment and compared lean and obese samples under fed or fasted conditions. These studies definitively addressed the alterations in subcellular structures in obesity and upon fasting, demonstrated that molecular subcellular architecture serves as a highly dynamic regulator of metabolic homeostasis, and identified the membrane shaping proteins that are involved in this critical architectural plasticity.  We have also examined the impact of feeding and fasting cycles on molecular architecture in detail and definitely addressed the nature of MAMs in physiology and obesity in very large data sets and explored other aspects of structural regulation in metabolic context.  These studies also gave us an opportunity to gather a diverse set of collaborations and technologies from optics to artificial intelligence-machine learning to graphic-media arts, and from cell biology to whole animal physiology (https://refikanadol.com/works/sense-of-space-molecular-architecture).

We are now interested in exploring other critical metabolic cells for their subcellular structural constellations and the dynamics of these features in the context of metabolic homeostasis.  One of our goals is to understand the hormonal or nutritional signals that utilize structural regulation to generate their metabolic effects, and if so, through which molecular mechanisms.  Finally, we explore these structural parameters in experimental models as well as human liver tissue and their relevance to pathologies associated with obesity and aging.

Regulation of ER Calcium Homeostasis and Mitochondrial ROS production

While the ER is equipped with powerful adaptive programs to preserve its integrity, it succumbs to metabolic stress, such as the case in obesity.  To understand the molecular mechanisms behind this maladaptive state of ER facing metabolic stress, we have systematically explored all ER resident proteins, membrane lipids, as well as ER-associated ribosomes and translational profiles in highly purified ER fractions in liver tissue and compared the compositional alterations in lean and obese state. 

These efforts illustrated that calcium regulation is aberrant in the ER, highlighted the impact of lipogenesis and changes in the ER membrane composition of phospholipids in impairing SERCA function in the liver during obesity. Interestingly, hepatocyte Ca+2 fluxes through the IP3Rs as well as store operated calcium entry (SOCE) are also impaired in obesity contributing to the metabolic pathologies.  We explore how disruption of calcium homeostasis can lead to hallmarks of obesity and diabetes: increased ER stress, metaflammation, increased glucose production, abrogated insulin sensitivity and abnormal lipid metabolism with a focus on ER and mitochondria calcium regulatory proteins during metabolic fluctuations and challenges.  We hope to learn more about the metabolic effects of this versatile signaling molecules and examine potential alterations in other tissues, such as adipose tissue, that are important for our body’s metabolic mission.

Finally, we study mitochondrial dysfunction and ROS production, both as related to abnormal interorganelle communication and to the activity of the mitochondrial electron transfer chain in obesity.  Most recently, we made an interesting observation that in obesity, excess ROS production in hepatic mitochondria occurs only through Complex 1 and described a mechanism for this unusual abnormal activity. We hope to utilize this knowledge to create potential novel therapeutics that involve proper regulation of organelle function in metabolic diseases. ​

Read more about the Hotamışlıgil Lab’s collaboration with artist Refik Anadol and the creation of the “Sense of Space Molecular Architecture Exhibit” here.

Suggested Readings

Parlakgül G, Pang S, Artico LL, Min N, Cagampan E, Villa R, Goncalves RLS, Lee GY, Xu CS, Hotamışlıgil GS, Arruda AP. Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity. Nat Commun. 2024 May 10;15(1):3982. doi: 10.1038/s41467-024-48272-7. PMID: 38729945 

Fu S, Yang L, Li P, Hofmann O, Dicker L, Hide W, Lin X, Watkins SM, Ivanov AR, Hotamisligil GS. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature. 2011 May 26;473(7348):528-31. doi: 10.1038/nature09968. Abstract

Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Görgün CZ, Hotamisligil GS. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006 Aug 25;313(5790):1137-40. doi: 10.1126/science.1128294. Abstract

Arruda AP, Pers BM, Parlakgül G, Güney E, Inouye K, Hotamisligil GS. Chronic enrichment of hepatic endoplasmic reticulum-mitochondria contact leads to mitochondrial dysfunction in obesity. Nat Med. 2014 Dec;20(12):1427-35. doi: 10.1038/nm.3735. Full Text

Parlakgül G, Arruda AP, Pang S, Cagampan E, Min N, Güney E, Lee GY, Inouye K, Hess HF, Xu CS, Hotamışlıgil GS. Regulation of liver subcellular architecture controls metabolic homeostasis. Nature. 2022 Mar;603(7902):736-742. doi: 10.1038/s41586-022-04488-5. Full Text

Goncalves RLS, Wang ZB, Inouye KE, Lee GY, Fu X, Saksi J, Rosique C, Parlakgul G, Arruda AP, Hui ST, Loperena MC, Burgess SC, Graupera I, Hotamisligil GS. Ubiquinone deficiency drives reverse electron transport to disrupt hepatic metabolic homeostasis in obesity. bioRxiv [Preprint]. doi: 10.1101/2023.02.21.528863. Full Text

Arruda AP, Pers BM, Parlakgul G, Güney E, Goh T, Cagampan E, Lee GY, Goncalves RL, Hotamisligil GS. Defective STIM-mediated store operated Ca2+ entry in hepatocytes leads to metabolic dysfunction in obesity. Elife. 2017 Dec 15;6:e29968. doi: 10.7554/eLife.29968. Full Text

Fu S, Yalcin A, Lee GY, Li P, Fan J, Arruda AP, Pers BM, Yilmaz M, Eguchi K, Hotamisligil GS. Phenotypic assays identify azoramide as a small-molecule modulator of the unfolded protein response with antidiabetic activity. Sci Transl Med. 2015 Jun 17;7(292):292ra98. doi: 10.1126/scitranslmed.aaa9134. Abstract

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