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Intermittent fasting promotes adipocyte mitochondrial fusion through Sirt3-mediated deacetylation of Mdh2
Published online by Cambridge University Press: 23 February 2023
Abstract
Fat deposition and lipid metabolism are closely related to the morphology, structure and function of mitochondria. The morphology of mitochondria between fusion and fission processes is mainly regulated by protein posttranslational modification. Intermittent fasting (IF) promotes high expression of Sirtuin 3 (Sirt3) and induces mitochondrial fusion in high-fat diet (HFD)-fed mice. However, the mechanism by which Sirt3 participates in mitochondrial protein acetylation during IF to regulate mitochondrial fusion and fission dynamics remains unclear. This article demonstrates that IF promotes mitochondrial fusion and improves mitochondrial function in HFD mouse inguinal white adipose tissue. Proteomic sequencing revealed that IF increased protein deacetylation levels in HFD mice and significantly increased Sirt3 mRNA and protein expression. After transfecting with Sirt3 overexpression or interference vectors into adipocytes, we found that Sirt3 promoted adipocyte mitochondrial fusion and improved mitochondrial function. Furthermore, Sirt3 regulates the JNK-FIS1 pathway by deacetylating malate dehydrogenase 2 (MDH2) to promote mitochondrial fusion. In summary, our study indicates that IF promotes mitochondrial fusion and improves mitochondrial function by upregulating the high expression of Sirt3 in HFD mice, promoting deacetylation of MDH2 and inhibiting the JNK-FIS1 pathway. This research provides theoretical support for studies related to energy limitation and animal lipid metabolism.
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- © The Author(s), 2023. Published by Cambridge University Press on behalf of The Nutrition Society
References
Bhargava, P & Schnellmann, R (2017) Mitochondrial energetics in the kidney. Nat Rev Nephrol 13, 629–646.CrossRefGoogle ScholarPubMed
Mansouri, A, Gattolliat, C & Asselah, T (2018) Mitochondrial dysfunction and signaling in chronic liver diseases. Gastroenterology 155, 629–647.CrossRefGoogle ScholarPubMed
Li, Q, Gao, Z, Chen, Y, et al. (2017) The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells. Protein Cell 8, 439–445.CrossRefGoogle ScholarPubMed
Von Stockum, S, Nardin, A, Schrepfer, E, et al. (2016) Mitochondrial dynamics and mitophagy in Parkinson’s disease: a fly point of view. Neurobiol Dis 90, 58–67.CrossRefGoogle ScholarPubMed
Chaudhari, SN & Kipreos, ET (2017) Increased mitochondrial fusion allows the survival of older animals in diverse C. elegans longevity pathways. Nat Commun 8, 182.CrossRefGoogle ScholarPubMed
Losón, OC, Song, Z, Chen, H, et al. (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24, 659–667.CrossRefGoogle ScholarPubMed
Dalmasso, G, Marin Zapata, PA, Brady, NR, et al. (2017) Agent-based modeling of mitochondria links sub-cellular dynamics to cellular homeostasis and heterogeneity. PLoS ONE 12, e0168198.CrossRefGoogle ScholarPubMed
Liesa, M & Shirihai, OS (2013) Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure. Cell Metab 17, 491–506.CrossRefGoogle ScholarPubMed
Rynders, CA, Thomas, EA, Zaman, A, et al. (2019) Effectiveness of intermittent fasting and time-restricted feeding compared to continuous energy restriction for weight loss. Nutrients 11, 2442.CrossRefGoogle ScholarPubMed
Baumeier, C, Kaiser, D, Heeren, J, et al. (2015) Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice. BBA 1851, 566–576.Google ScholarPubMed
Yang, W, Cao, M, Mao, X, et al. (2016) Alternate-day fasting protects the livers of mice against high-fat diet-induced inflammation associated with the suppression of Toll-like receptor 4/nuclear factor κB signaling. Nutr Res 36, 586–593.CrossRefGoogle ScholarPubMed
Weir, HJ, Yao, P, Huynh, FK, et al. (2017) Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling. Cell Metab 26, 884–896.CrossRefGoogle ScholarPubMed
Liu, Y, Cheng, A, Li, YJ, et al. (2019) SIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice. Nat Commun 10, 1886.CrossRefGoogle ScholarPubMed
Zhang, Y, Zhou, F, Bai, M, et al. (2019) The pivotal role of protein acetylation in linking glucose and fatty acid metabolism to β-cell function. Cell Death Dis 10, 66.CrossRefGoogle ScholarPubMed
Shimazu, T, Hirschey, MD, Hua, L, et al. (2010) SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 12, 654–661.CrossRefGoogle ScholarPubMed
De Marchi, U, Galindo, AN, Thevenet, J, et al. (2019) Mitochondrial lysine deacetylation promotes energy metabolism and calcium signaling in insulin-secreting cells. FASEB J 33, 4660–4674.CrossRefGoogle ScholarPubMed
Tsuda, M, Fukushima, A, Matsumoto, J, et al. (2018) Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure. J Cachexia Sarcopenia Muscle 9, 844–859.CrossRefGoogle ScholarPubMed
Osborne, B, Cooney, GJ & Turner, N (2014) Are sirtuin deacylase enzymes important modulators of mitochondrial energy metabolism? BBA 1840, 1295–1302.Google ScholarPubMed
Zhang, Y, Wen, P, Luo, J, et al. (2021) Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis. Cell Death Dis 12, 847.CrossRefGoogle ScholarPubMed
Samant, SA, Zhang, HJ, Hong, Z, et al. (2014) SIRT3 deacetylates and activates OPA1 to regulate mitochondrial dynamics during stress. Mol Cell Biol 34, 807–819.CrossRefGoogle ScholarPubMed
Herr, DJ, Baarine, M, Aune, SE, et al. (2018) HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury. J Mol Cell Cardiol 114, 309–319.CrossRefGoogle Scholar
Herr, DJ, Singh, T, Dhammu, T, et al. (2020) Regulation of metabolism by mitochondrial enzyme acetylation in cardiac ischemia-reperfusion injury. Biochim Biophys Acta Mol Basis Dis 1866, 165728.CrossRefGoogle ScholarPubMed
Xiao, H, Wang, J, Yuan, L, et al. (2013) Chicoric acid induces apoptosis in 3T3-L1 preadipocytes through ROS-mediated PI3K/Akt and MAPK signaling pathways. J Agric Food Chem 61, 1509–1520.CrossRefGoogle ScholarPubMed
Laursen, NB, Kessler, R, Fröhli, E, et al. (1998) Effects of ras transformation on the induction of the IL-1 receptor related T1 gene in response to mitogens, anisomycin, IL-1 and TNFα
. Oncogene 16, 575–586.CrossRefGoogle ScholarPubMed
Gómez-Valadés, AG, Pozo, M, Varela, L, et al. (2021) Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca(2+) homeostasis with adipose tissue lipolysis. Cell Metab 33, 1820–1835.CrossRefGoogle ScholarPubMed
Wei, D, Li, Y, Che, M, et al. (2022) Melatonin relieves hepatic lipid dysmetabolism caused by aging via modifying the secondary bile acid pattern of gut microbes. Cell Mol Life Sci 79, 527.CrossRefGoogle ScholarPubMed
Hepler, C, Weidemann, BJ, Waldeck, NJ, et al. (2022) Time-restricted feeding mitigates obesity through adipocyte thermogenesis. Science 378, 276–284.CrossRefGoogle ScholarPubMed
Chan, DC (2020) Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol 15, 235–259.CrossRefGoogle ScholarPubMed
Wang, T, Cao, Y, Zheng, Q, et al. (2019) SENP1-Sirt3 signaling controls mitochondrial protein acetylation and metabolism. Mol Cell 75, 823–834.CrossRefGoogle ScholarPubMed
Yang, H, Yang, T, Baur, JA, et al. (2007) Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival. Cell 130, 1095–1107.CrossRefGoogle ScholarPubMed
Ahmed, B, Sultana, R & Greene, MW (2021) Adipose tissue and insulin resistance in obese. Biomed Pharmacother 137, 111315.CrossRefGoogle ScholarPubMed
Yao, X, Jing, X, Guo, J, et al. (2019) Icariin protects bone marrow mesenchymal stem cells against iron overload induced dysfunction through mitochondrial fusion and fission, PI3K/AKT/mTOR and MAPK pathways. Front Pharmacol 10, 163.CrossRefGoogle ScholarPubMed
Garza-González, S, Nieblas, B, Solbes-Gochicoa, MM, et al. (2022) Intermittent fasting as possible treatment for heart failure. Curr Vasc Pharmacol 20, 260–271.Google ScholarPubMed
Varady, KA, Bhutani, S, Klempel, MC, et al. (2013) Alternate day fasting for weight loss in normal weight and overweight subjects: a randomized controlled trial. Nutr J 12, 146.CrossRefGoogle ScholarPubMed
Patterson, RE & Sears, DD (2017) Metabolic effects of intermittent fasting. Annu Rev Nutr 37, 371–393.CrossRefGoogle ScholarPubMed
Mattson, MP, Moehl, K, Ghena, N, et al. (2018) Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci 19, 63–80.CrossRefGoogle ScholarPubMed
Wilhelmi de Toledo, F, Grundler, F, Bergouignan, A, et al. (2019) Safety, health improvement and well-being during a 4 to 21-d fasting period in an observational study including 1422 subjects. PLoS ONE 14, e0209353.CrossRefGoogle Scholar
Zhang, X, Gao, T, Deng, S, et al. (2021) Fasting induces hepatic lipid accumulation by stimulating peroxisomal dicarboxylic acid oxidation. J Biol Chem 296, 100622.CrossRefGoogle ScholarPubMed
Annesley, SJ & Fisher, PR (2019) Mitochondria in health and disease. Cells 8, 680.CrossRefGoogle ScholarPubMed
Kelley, DE, He, J, Menshikova, EV, et al. (2002) Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 51, 2944–2950.CrossRefGoogle ScholarPubMed
Kim, YH, Lee, JH, Yeung, JL, et al. (2019) Thermogenesis-independent metabolic benefits conferred by isocaloric intermittent fasting in ob/ob mice. Sci Rep 9, 2479.CrossRefGoogle ScholarPubMed
Wu, MT, Chou, HN & Huang, CJ (2014) Dietary fucoxanthin increases metabolic rate and upregulated mRNA expressions of the PGC-1α network, mitochondrial biogenesis and fusion genes in white adipose tissues of mice. Mar Drugs 12, 964–982.CrossRefGoogle ScholarPubMed
Lee, JH, Park, A, Oh, KJ, et al. (2019) The role of adipose tissue mitochondria: regulation of mitochondrial function for the treatment of metabolic diseases. Int J Mol Sci 20, 4924.CrossRefGoogle ScholarPubMed
Uddin, GM, Youngson, NA, Doyle, BM, et al. (2017) Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise. Sci Rep 7, 15063.CrossRefGoogle ScholarPubMed
Santos, HO & Macedo, RCO (2018) Impact of intermittent fasting on the lipid profile: assessment associated with diet and weight loss. Clin Nutr ESPEN 24, 14–21.CrossRefGoogle ScholarPubMed
Hanjani, N, Zamaninour, N, Najibi, N, et al. (2021) The effects of calorie restriction and time-restricted feeding on IGF1 serum level and lipid profile in male Wister rats with previous obesity. Int J Prev Med 12, 157.Google ScholarPubMed
Hammer, SS, Vieira, CP, McFarland, D, et al. (2021) Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction. Diabetologia 64, 1674–1689.CrossRefGoogle ScholarPubMed
Dai, S, Wei, J, Zhang, H, et al. (2022) Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway. J Neuroinflam 19, 122.CrossRefGoogle ScholarPubMed
Hirschey, MD, Shimazu, T, Goetzman, E, et al. (2010) SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125.CrossRefGoogle ScholarPubMed
Schwer, B, North, BJ, Frye, RA, et al. (2002) The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. J Cell Biol 158, 647–657.CrossRefGoogle ScholarPubMed
Peng, C, Lu, Z, Xie, Z, et al. (2011) The first identification of lysine malonylation substrates and its regulatory enzyme. Mol Cell Proteomics 10(12), M111.012658.CrossRefGoogle ScholarPubMed
Lombard, DB, Alt, FW, Cheng, HL, et al. (2007) Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol Cell Biol 27, 8807–8814.CrossRefGoogle ScholarPubMed
Sun, W, Liu, C, Chen, Q, et al. (2018) SIRT3: a new regulator of cardiovascular diseases. Oxid Med Cell Longevity 2018, 7293861.CrossRefGoogle ScholarPubMed
Wang, Q, Xu, J, Li, X, et al. (2019) Sirt3 modulate renal ischemia-reperfusion injury through enhancing mitochondrial fusion and activating the ERK-OPA1 signaling pathway. J Cell Physiol 234, 23495–23506.CrossRefGoogle ScholarPubMed
Wu, X, Luo, J, Liu, H, et al. (2020) SIRT3 protects against early brain injury following subarachnoid hemorrhage via promoting mitochondrial fusion in an AMPK dependent manner. Chin Neurosurg J 6, 1.CrossRefGoogle Scholar
Zhao, D, Sun, Y, Tan, Y, et al. (2018) Short-duration swimming exercise after myocardial infarction attenuates cardiac dysfunction and regulates mitochondrial quality control in aged mice. Oxid Med Cell Longevity 2018, 4079041.CrossRefGoogle ScholarPubMed
Rardin, MJ, Newman, JC, Held, JM, et al. (2013) Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways. Proc Natl Acad Sci USA 110, 6601–6606.CrossRefGoogle ScholarPubMed
Minárik, P, Tomásková, N, Kollárová, M, et al. (2002) Malate dehydrogenases – structure and function. Gen Physiol Biophys 21, 257–265.Google ScholarPubMed
Kim, EY, Han, BS, Kim, WK, et al. (2013) Acceleration of adipogenic differentiation via acetylation of malate dehydrogenase 2. Biochem Biophys Res Commun 441, 77–82.CrossRefGoogle ScholarPubMed
Yang, H, Zhou, L, Shi, Q, et al. (2015) SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth. EMBO J 34, 1110–1125.CrossRefGoogle ScholarPubMed
Guo, X, Jiang, X, Chen, K, et al. (2022) The role of palmitoleic acid in regulating hepatic gluconeogenesis through SIRT3 in obese mice. Nutrients 14, 1482.CrossRefGoogle ScholarPubMed
Liang, Q, Benavides, GA, Vassilopoulos, A, et al. (2013) Bioenergetic and autophagic control by Sirt3 in response to nutrient deprivation in mouse embryonic fibroblasts. Biochem J 454, 249–257.CrossRefGoogle ScholarPubMed
Yang, Y, Gong, Z & Wang, Z (2019) Yes-associated protein reduces neuroinflammation through upregulation of Sirt3 and inhibition of JNK signaling pathway. J Recept Signal Transduct Res 39, 479–487.CrossRefGoogle ScholarPubMed
Ravi, R & Subramaniam Rajesh, B (2022) Paraoxonase 2 protects against the CML mediated mitochondrial dysfunction through modulating JNK pathway in human retinal cells. Biochim Biophys Acta Gen Subj 1866, 130043.CrossRefGoogle ScholarPubMed
Naia, L, Carmo, C, Campesan, S, et al. (2021) Mitochondrial SIRT3 confers neuroprotection in Huntington’s disease by regulation of oxidative challenges and mitochondrial dynamics. Free Radic Biol Med 163, 163–179.CrossRefGoogle ScholarPubMed
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