bims-mimead Biomed News
on Mitochondrial metabolism in ageing and metabolic disease
Issue of 2024–11–03
thirteen papers selected by
Rachel M. Handy, University of Guelph
  1. [Research progress in the regulation of functional homeostasis of adipose tissue by exosomal miRNA].
  2. Human peripancreatic adipose tissue paracrine signaling impacts insulin secretion, blood flow, and gene transcription.
  3. Microarray Analysis of Visceral Adipose Tissue in Obese Women Reveals Common Crossroads Among Inflammation, Metabolism, Addictive Behaviors, and Cancer: AKT3 and MAPK1 Cross Point in Obesity.
  4. Hoxa5 alleviates adipose tissue metabolic distortions in high-fat diet mice associated with a reduction in MERC.
  5. Branched-chain amino acid metabolism: Pathophysiological mechanism and therapeutic intervention in metabolic diseases.
  6. Reducing the mitochondrial oxidative burden alleviates lipid-induced muscle insulin resistance in humans.
  7. Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.
  8. Tirzepatide's role in targeting adipose tissue macrophages to reduce obesity-related inflammation and improve insulin resistance.
  9. GDF15 is still a mystery hormone.
  10. ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis.
  11. [Research progress of the effects of high-intensity interval training on excess post-exercise oxygen consumption in human].
  12. Autophagy Alterations in White and Brown Adipose Tissues of Mice Exercised under Different Training Protocols.
  13. Mitochondrial inhibitors reveal roles of specific respiratory chain complexes in CRY-dependent degradation of TIM.
  1. Sheng Li Xue Bao. 2024 Oct 25. 76(5): 791-800
    [Research progress in the regulation of functional homeostasis of adipose tissue by exosomal miRNA].
    Jun-Qing Xu, Meng-Xin Jiang, Ying-Jiang Xu, Sheng-Jun Dong.
      Adipose tissue holds a pivotal position in maintaining systemic energy homeostasis. Brown adipose tissue (BAT) expresses uncoupling protein 1 (UCP1), which is specialized in dissipating chemical energy as heat to maintain euthermia, a process called non-shivering thermogenesis. Conversely, white adipocyte (WAT) predominantly serves as the primary reservoir for energy storage, while also exhibiting endocrine activity by secreting various adipokines, thereby modulating systemic metabolism. Under the stimulation of cold exposure, physical activity and pharmacological intervention, WAT can occur as "browning" or "beiging", and transform into beige adipose tissue. The morphology and function of beige adipocyte are similar to brown adipocyte, both of which express higher levels of UCP1 and also have the function of thermogenesis. Thus, exploring methods to regulate the functional homeostasis of adipose tissue and its underlying molecular mechanisms hold promise for advancing preventative and therapeutic approaches against metabolic diseases. Exosomes, a subtype of extracellular vesicles (EVs) with a diameter of 40-100 nm, facilitate intercellular communication in obese individuals and exert significant influence on insulin resistance and impaired glucose tolerance within adipose tissue. These effects are primarily mediated by microRNA (miRNA) transported by exosomes. MiRNA, originating from various cellular sources, traverses between different cell types via EVs, thereby orchestrating reciprocal functional modulation among diverse tissues and organs. This review systematically summarized the research progress in exosomal miRNA-mediated regulation of adipose tissue functional homeostasis, with the aim of offering novel insights into the diagnosis and treatment of obesity and associated metabolic diseases.
  2. J Clin Endocrinol Metab. 2024 Nov 01. pii: dgae767. [Epub ahead of print]
    Human peripancreatic adipose tissue paracrine signaling impacts insulin secretion, blood flow, and gene transcription.
    Bryan C Bergman, Karin Zemski Berry, Amanda Garfield, Amy Keller, Simona Zarini, Sophia Bowen, Colleen McKenna, Darcy Kahn, Jay Pavelka, Emily Macias, Charis Uhlson, Chris Johnson, Holger A Russ, Carlos H Viesi, Marcus Seldin, Chengyang Liu, Nicolai Doliba, Jonathan Schoen, Kevin Rothchild, Kweku Hazel, Ali Naji.
       CONTEXT: Adipose tissue accumulation around non-adipose tissues is associated with obesity and metabolic disease. One relatively unstudied depot is peripancreatic adipose tissue (PAT) that accumulates in obesity and insulin resistance and may impact beta cell function. Pancreatic lipid accumulation and PAT content are negatively related to metabolic outcomes in humans, but these studies are limited by the inability to pursue mechanisms.
    OBJECTIVE: We obtained PAT from human donors through the Human Pancreas Analysis Program to evaluate differences in paracrine signaling compared to subcutaneous adipose tissue (SAT), as well as effects of the PAT secretome on aortic vasodilation, human islet insulin secretion, and gene transcription using RNAseq.
    RESULTS: PAT had greater secretion of IFN-γ and most inflammatory eicosanoids compared to SAT. Secretion of adipokines negatively related to metabolic health were also increased in PAT compared to SAT. We found no overall effects of PAT compared to SAT on human islet insulin secretion, however, insulin secretion was suppressed after PAT exposure from men compared to women. Vasodilation was significantly dampened by PAT conditioned media, an effect explained almost completely by PAT from men and not women. Islets treated with PAT showed selective changes in lipid metabolism pathways while SAT altered cellular signaling and growth. RNAseq analysis showed changes in islet gene transcription impacted by PAT compared to SAT, with the biggest changes found between PAT based on sex.
    CONCLUSION: The PAT secretome is metabolically negative compared to SAT, and impacts islet insulin secretion, blood flow, and gene transcription in a sex dependent manner.
    Keywords:  Insulin secretion; adipose secretome; beta cells; ectopic adipose tissue; human islets; obesity
    DOI:  https://doi.org/10.1210/clinem/dgae767
  3. J Obes. 2024 ;2024 4541071
    Microarray Analysis of Visceral Adipose Tissue in Obese Women Reveals Common Crossroads Among Inflammation, Metabolism, Addictive Behaviors, and Cancer: AKT3 and MAPK1 Cross Point in Obesity.
    Rolando Martínez-Romero, Susana Aideé González-Chávez, Victor Roberto Urías-Rubí, Víctor Manuel Gómez-Moreno, Manlio Favio Blanco-Cantero, Héctor Mario Bernal-Velázquez, Arturo Luévano-González, César Pacheco-Tena.
      Background: Visceral adipose tissue (VAT) abnormalities are directly associated with obesity-associated disorders. The underlying mechanisms that confer increased pathological risk to VAT in obesity have not been fully described. Methods: A case-control study was conducted that included 10 women with obesity (36.80 ± 7.39 years, BMI ≥ 30 kg/m2) and 10 women of normal weight (32.70 ± 9.45 years, BMI < 24.9 kg/m2). RNA was extracted from greater omentum biopsies, and, using a DNA microarray, differential transcriptomic expression of VAT in women with obesity was evaluated taking as a reference that of women with normal weight. The differentially expressed genes (DEGs) were classified into functional biological processes and signaling pathways; moreover, the protein-protein interaction (PPI) networks were integrated for a deeper analysis of the pathways and genes involved in the central obesity-associated disorders. The expression of TNF-α, MAPK, and AKT proteins was also quantified in VAT. Results: The VAT of women with obesity had 3808 DEGs, mainly associated with the cellular process of inflammation and carbohydrates and lipid metabolism. Overexpressed genes were associated with inflammatory, metabolic, hormonal, neuroendocrine, carcinogenic, and infectious pathways. Cellular processes related to addictive behaviors were notable. MAPK and PI3K-AKT pathways were overexpressed, and Mapk1 and Akt3 genes were common crossing points among obesity-associated disorders' pathways. The increased expression of MAPK, AKT, and TNF proteins was confirmed in the VAT of women with obesity. Conclusion: VAT confers a complex and blended pathogenic transcriptomic profile in obese patients, where abnormal processes are mainly controlled by activating intracellular signaling pathways that exhibit a high degree of redundancy. Identifying shared cross points between those pathways could allow specific targeting treatments to exert a widespread effect over multiple pathogenic processes.
    Keywords:  MAPK; PI3K/AKT/mTOR; adipocyte; microarray
    DOI:  https://doi.org/10.1155/2024/4541071
  4. BMC Biol. 2024 Oct 29. 22(1): 247
    Hoxa5 alleviates adipose tissue metabolic distortions in high-fat diet mice associated with a reduction in MERC.
    Qi Chen, Zeyu Ren, Liping Dang, Zunhai Liu, Simeng Wang, Xinhao Chen, Guiping Qiu, Chao Sun.
       BACKGROUND: Mitochondria-endoplasmic reticulum membrane contact (MERC) is an important mode of intercellular organelle communication and plays a crucial role in adipose tissue metabolism. Functionality of Hoxa5 is an important transcription factor involved in adipose tissue fate determination and metabolic regulation, but the relationship between Hoxa5 and MERC is not well understood.
    RESULTS: In our study, we established an obesity model mouse by high-fat diet (HFD), induced the alteration of Hoxa5 expression by adenoviral transfection, and explored the effect of Hoxa5 on MERC dysfunction and metabolic distortions of adipose tissue with the help of transmission electron microscopy, calcium ion probe staining, and other detection means. The results showed Hoxa5 was able to reduce MERC production, alleviate endoplasmic reticulum stress (ERS) and calcium over-transport, and affect cGAS-STING-mediated innate immune response affecting adipose tissue energy metabolism, as well as affect the AKT-IP3R pathway to alleviate insulin resistance and ameliorate metabolic distortions in adipose tissue of mice.
    CONCLUSIONS: Our results suggest that Hoxa5 can ameliorate high-fat diet-induced MERC overproduction and related functional abnormalities, in which finding is expected to provide new ideas for the improvement of obesity-related metabolic distortions.
    Keywords:  Calcium ion homeostasis; Hoxa5; Mitochondria-endoplasmic reticulum membrane contact (MERC)
    DOI:  https://doi.org/10.1186/s12915-024-02047-0
  5. Obes Rev. 2024 Oct 25. e13856
    Branched-chain amino acid metabolism: Pathophysiological mechanism and therapeutic intervention in metabolic diseases.
    Shama Mansoori, Melody Yuen-Man Ho, Kelvin Kwun-Wang Ng, Kenneth King-Yip Cheng.
      Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential for maintaining physiological functions and metabolic homeostasis. However, chronic elevation of BCAAs causes metabolic diseases such as obesity, type 2 diabetes (T2D), and metabolic-associated fatty liver disease (MAFLD). Adipose tissue, skeletal muscle, and the liver are the three major metabolic tissues not only responsible for controlling glucose, lipid, and energy balance but also for maintaining BCAA homeostasis. Under obese and diabetic conditions, different pathogenic factors like pro-inflammatory cytokines, lipotoxicity, and reduction of adiponectin and peroxisome proliferator-activated receptors γ (PPARγ) disrupt BCAA metabolism, leading to excessive accumulation of BCAAs and their downstream metabolites in metabolic tissues and circulation. Mechanistically, BCAAs and/or their downstream metabolites, such as branched-chain ketoacids (BCKAs) and 3-hydroxyisobutyrate (3-HIB), impair insulin signaling, inhibit adipogenesis, induce inflammatory responses, and cause lipotoxicity in the metabolic tissues, resulting in multiple metabolic disorders. In this review, we summarize the latest studies on the metabolic regulation of BCAA homeostasis by the three major metabolic tissues-adipose tissue, skeletal muscle, and liver-and how dysregulated BCAA metabolism affects glucose, lipid, and energy balance in these active metabolic tissues. We also summarize therapeutic approaches to restore normal BCAA metabolism as a treatment for metabolic diseases.
    Keywords:  BCAAs; adipose tissue; diabetes and obesity; liver; metabolic tissues; skeletal muscle
    DOI:  https://doi.org/10.1111/obr.13856
  6. Sci Adv. 2024 Nov;10(44): eadq4461
    Reducing the mitochondrial oxidative burden alleviates lipid-induced muscle insulin resistance in humans.
    Matteo Fiorenza, Johan Onslev, Carlos Henríquez-Olguín, Kaspar W Persson, Sofie A Hesselager, Thomas E Jensen, Jørgen F P Wojtaszewski, Morten Hostrup, Jens Bangsbo.
      Preclinical models suggest mitochondria-derived oxidative stress as an underlying cause of insulin resistance. However, it remains unknown whether this pathophysiological mechanism is conserved in humans. Here, we used an invasive in vivo mechanistic approach to interrogate muscle insulin action while selectively manipulating the mitochondrial redox state in humans. To this end, we conducted insulin clamp studies combining intravenous infusion of a lipid overload with intake of a mitochondria-targeted antioxidant (mitoquinone). Under lipid overload, selective modulation of mitochondrial redox state by mitoquinone enhanced insulin-stimulated glucose uptake in skeletal muscle. Mechanistically, mitoquinone did not affect canonical insulin signaling but augmented insulin-stimulated glucose transporter type 4 (GLUT4) translocation while reducing the mitochondrial oxidative burden under lipid oversupply. Complementary ex vivo studies in human muscle fibers exposed to high intracellular lipid levels revealed that mitoquinone improves features of mitochondrial bioenergetics, including diminished mitochondrial H2O2 emission. These findings provide translational and mechanistic evidence implicating mitochondrial oxidants in the development of lipid-induced muscle insulin resistance in humans.
    DOI:  https://doi.org/10.1126/sciadv.adq4461
  7. Nat Metab. 2024 Oct 31.
    Skeletal muscle from TBC1D4 p.Arg684Ter variant carriers is severely insulin resistant but exhibits normal metabolic responses during exercise.
    Jonas M Kristensen, Rasmus Kjøbsted, Trine J Larsen, Christian S Carl, Janne R Hingst, Johan Onslev, Jesper B Birk, Anette Thorup, Dorte E Steenberg, Jonas R Knudsen, Nicolai S Henriksen, Elise J Needham, Jens F Halling, Anders Gudiksen, Carsten F Rundsten, Kristian E Hanghøj, Sara E Stinson, Birgitte Hoier, Camilla C Hansen, Thomas E Jensen, Ylva Hellsten, Henriette Pilegaard, Niels Grarup, Jesper Olesen, Sean J Humphrey, David E James, Michael L Pedersen, Erik A Richter, Torben Hansen, Marit E Jørgensen, Jørgen F P Wojtaszewski.
      In the Greenlandic Inuit population, 4% are homozygous carriers of a genetic nonsense TBC1D4 p.Arg684Ter variant leading to loss of the muscle-specific isoform of TBC1D4 and an approximately tenfold increased risk of type 2 diabetes1. Here we show the metabolic consequences of this variant in four female and four male homozygous carriers and matched controls. An extended glucose tolerance test reveals prolonged hyperglycaemia followed by reactive hypoglycaemia in the carriers. Whole-body glucose disposal is impaired during euglycaemic-hyperinsulinaemic clamp conditions and associates with severe insulin resistance in skeletal muscle only. Notably, a marked reduction in muscle glucose transporter GLUT4 and associated proteins is observed. While metabolic regulation during exercise remains normal, the insulin-sensitizing effect of a single exercise bout is compromised. Thus, loss of the muscle-specific isoform of TBC1D4 causes severe skeletal muscle insulin resistance without baseline hyperinsulinaemia. However, physical activity can ameliorate this condition. These observations offer avenues for personalized interventions and targeted preventive strategies.
    DOI:  https://doi.org/10.1038/s42255-024-01153-1
  8. Int Immunopharmacol. 2024 Oct 28. pii: S1567-5769(24)02021-6. [Epub ahead of print]143(Pt 2): 113499
    Tirzepatide's role in targeting adipose tissue macrophages to reduce obesity-related inflammation and improve insulin resistance.
    Yin Xia, Jing Jin, Yaqin Sun, Xiaocen Kong, Ziyang Shen, Rengna Yan, Rong Huang, Xiaomei Liu, Wenqing Xia, Jingjing Ma, Xudong Zhu, Qian Li, Jianhua Ma.
       BACKGROUND: Obesity and type 2 diabetes mellitus (T2DM) are significant global health challenges, with adipose tissue inflammation being a pivotal contributor to metabolic dysfunction. The involvement of adipose tissue macrophages (ATMs) in obesity-associated inflammation is well recognized, yet the therapeutic strategies specifically targeting ATM-mediated inflammation remain limited.
    OBJECTIVE: This study aims to explore the effects of tirzepatide, a novel dual GLP-1 and GIP receptor agonist, on ATMs, adipose tissue inflammation, and insulin resistance in the context of obesity.
    METHODS: Obese mouse models were established through high-fat diet feeding and subsequently treated with tirzepatide at a dose of 1.2 mg/kg twice weekly for 12 weeks. The study assessed the impact on ATM phenotype, inflammatory markers, and key metabolic indicators.
    RESULTS: Tirzepatide treatment significantly mitigated the infiltration of pro-inflammatory M1 ATMs within adipose tissue and concurrently reduced levels of inflammatory cytokines, thereby enhancing insulin sensitivity. Tirzepatide demonstrated therapeutic efficacy through its modulation of the ERK signaling pathway and promotion of M1-type macrophage apoptosis.
    CONCLUSION: Tirzepatide's potential as a therapeutic strategy for addressing metabolic diseases associated with obesity and T2DM by targeting ATM activity and mitigating obesity-associated inflammation.
    Keywords:  Adipose tissue inflammation; ERK signaling pathway; Macrophages; Obesity; Tirzepatide
    DOI:  https://doi.org/10.1016/j.intimp.2024.113499
  9. Trends Endocrinol Metab. 2024 Oct 29. pii: S1043-2760(24)00254-6. [Epub ahead of print]
    GDF15 is still a mystery hormone.
    Casper M Sigvardsen, Michael M Richter, Sarah Engelbeen, Maximilian Kleinert, Erik A Richter.
      Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor-β (TGF-β) superfamily. Despite its identification over 20 years ago, the functions of GDF15 remain complex and not fully elucidated. Its concentration in plasma varies widely depending on the physiological and pathophysiological state of the organism. GDF15 has been described to regulate food intake and insulin sensitivity in rodents via the GDNF family receptor α-like (GFRAL) receptor, and to be elevated in pregnancy and many disease states and decreased in physically fit individuals. We discuss the latest developments in the regulation of GDF15 secretion and its diverse physiological effects, and touch upon possible GFRAL-independent effects of GDF15. In addition, we discuss the effects of proteins and peptides derived from the same precursor protein as GDF15.
    Keywords:  appetite; energy expenditure; insulin sensitivity; weight loss
    DOI:  https://doi.org/10.1016/j.tem.2024.09.002
  10. J Lipid Res. 2024 Oct 29. pii: S0022-2275(24)00185-8. [Epub ahead of print] 100680
    ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis.
    Qing Liu, Xiaolin Wu, Wei Duan, Xiaohan Pan, Martin Wabitsch, Ming Lu, Jing Li, Li-Hao Huang, Zhangsen Zhou, Yuyan Zhu.
      Maintaining cholesterol homeostasis is critical for preserving adipocyte function during the progression of obesity. Despite this, the regulatory role of cholesterol esterification in governing adipocyte expandability has been understudied. Acyl-coenzyme A (CoA):cholesterol acyltransferase / Sterol O-acyltransferase 1 (ACAT1/SOAT1) is the dominant enzyme to synthesize cholesteryl ester in most tissues. Our previous study demonstrated that knockdown of either ACAT1 or ACAT2 impaired adipogenesis. However, the underlying mechanism of how ACAT1 mediates adipogenesis remains unclear. Here, we reported that ACAT1 is the dominant isoform in white adipose tissue of both humans and mice and knocking out ACAT1 reduced fat mass in mice. Furthermore, ACAT1-deficiency inhibited the early stage of adipogenesis via attenuating PPARγ pathway. Mechanistically, ACAT1 deficiency inhibited SREBP2-mediated cholesterol uptake and thus reduced intracellular and plasma membrane cholesterol level during adipogenesis. While replenishing cholesterol could rescue adipogenic master gene - Pparγ's transcription in ACAT1 deficient cells during adipogenesis. Finally, overexpression of catalytically functional ACAT1, not the catalytic-dead ACAT1, rescued cholesterol level and efficiently rescued the transcription of PPARγ, as well as the adipogenesis in ACAT1-deficient preadipocytes. In summary, our study revealed the indispensable role of ACAT1 in adipogenesis via regulating intracellular cholesterol homeostasis.
    Keywords:  Adipocytes; Cholesterol/Metabolism; Cholesterol/Trafficking; Cholesteryl ester; Lipid rafts; Nuclear receptors/SREBP; PPARγ
    DOI:  https://doi.org/10.1016/j.jlr.2024.100680
  11. Sheng Li Xue Bao. 2024 Oct 25. 76(5): 849-861
    [Research progress of the effects of high-intensity interval training on excess post-exercise oxygen consumption in human].
    Yang-Yang Su, Xiao-Ning Dong, Xiu-Qin Wu.
      Elevated human metabolism during recovery is associated with increased excess post-exercise oxygen consumption (EPOC). EPOC is linearly related to exercise duration and exponentially related to exercise intensity. It is commonly believed that near-maximal intensity interval training prompts the body to produce greater EPOC. This review focuses on the origin and development of high-intensity interval training (HIIT), analyzes its concept, classification and function, and discusses its effects on human EPOC. HIIT promotes a significant increase in EPOC during the fast recovery period, whereas the changes of EPOC during the slow recovery period are still inconclusive; Sprint interval training (SIT) promotes a significant increase in EPOC throughout the whole recovery period. Compared with HIIT, the body's energy expenditure and oxygen uptake (VO2) increase significantly during moderate-intensity continuous training (MICT), but the total energy expenditure and VO2 during exercise and 24 h of recovery period are similar between the two types of exercises, indicating that greater EPOC is generated during the recovery period of HIIT. The mechanisms by which interval training improves EPOC include increasing lung ventilation and catecholamine secretion, accelerating systemic circulation, increasing body temperature, promoting glycogen resynthesis, rapid recruitment of fast twitch muscle fibers and uncoupling of mitochondrial respiration, up-regulating hypoxia inducible factor-1 alpha and skeletal muscle protein, as well as improving intestinal flora.
  12. Front Biosci (Landmark Ed). 2024 Oct 08. 29(10): 348
    Autophagy Alterations in White and Brown Adipose Tissues of Mice Exercised under Different Training Protocols.
    Isaac Tamargo-Gómez, Manuel Fernández-Sanjurjo, Helena Codina-Martínez, Cristina Tomás-Zapico, Eduardo Iglesias-Gutiérrez, Benjamín Fernández-García, Álvaro F Fernández.
       BACKGROUND: Autophagy is a conserved catabolic process that promotes cellular homeostasis and health. Although exercise is a well-established inducer of this pathway, little is known about the effects of different types of training protocols on the autophagy levels of tissues that are tightly linked to age-related metabolic syndromes (like brown adipose tissue) but are not easily accessible in humans.
    METHODS: Here, we take advantage of animal models to assess the effects of short- and long-term resistance and endurance training in both white and brown adipose tissue, reporting distinct alterations on autophagy proteins microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B, or LC3B) and sequestosome-1 (SQSTM1/p62). Additionally, we also analyzed the repercussions of these interventions in fat tissues of mice lacking autophagy-related protein 4 homolog B (ATG4B), further assessing the impact of exercise in these dynamic, regulatory organs when autophagy is limited.
    RESULTS: In wild-type mice, both short-term endurance and resistance training protocols increased the levels of autophagy markers in white adipose tissue before this similarity diverges during long training, while autophagy regulation appears to be far more complex in brown adipose tissue. Meanwhile, in ATG4B-deficient mice, only resistance training could slightly increase the presence of lipidated LC3B, while p62 levels increased in white adipose tissue after short-term training but decreased in brown adipose tissue after long-term training.
    CONCLUSIONS: Altogether, our study suggests an intricated regulation of exercise-induced autophagy in adipose tissues that is dependent on the training protocol and the autophagy competence of the organism.
    Keywords:  ATG4B; LC3B; adipose tissue; autophagy; endurance training; exercise; p62; resistance training
    DOI:  https://doi.org/10.31083/j.fbl2910348
  13. Sci Rep. 2024 10 30. 14(1): 26051
    Mitochondrial inhibitors reveal roles of specific respiratory chain complexes in CRY-dependent degradation of TIM.
    Xiangzhong Zheng, Dechun Chen, Brian Zoltowski, Amita Sehgal.
      Drosophila Cryptochrome (CRY) is an essential photoreceptor that mediates the resetting of the circadian clock by light. in vitro studies demonstrated a critical role of redox cycling of the FAD cofactor for CRY activation by light. However, it is unknown if CRY responds to cellular redox environment to modulate the circadian clock. We report here that the mitochondrial respiratory chain impinges on CRY activity. Inhibition of complex III and V blocks CRY-mediated degradation of TIMELESS (TIM) in response to light, and also blocks light-induced CRY degradation. On the other hand, inhibition of complex I facilitates TIM degradation even in the dark. Mutations of critical residues of the CRY C-terminus promote TIM degradation in the dark, even in the presence of complex III and V inhibitors. We propose that complex III and V activities are important for activation of CRY in response to light. Interestingly, we found that transcriptional repressor functions of Drosophila and mammalian CRY proteins are not affected by mitochondrial inhibitors. Together these data suggest that the two functions of CRY have different sensitivity to disruptions of the mitochondrial respiratory chain: one is sensitive to mitochondrial activities that enable resetting, the other is insensitive so as to sustain the molecular oscillator.
    Keywords:  Circadian clock; Cryptochrome; Mitochondria; Respiratory chain; Timeless
    DOI:  https://doi.org/10.1038/s41598-024-77692-0
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