Skip to main content
Hauptrubriken
CME Facharzt-Training Webinare Zeitschriften Bücher e.Medpedia Podcast
Service
Jobbörse Info & Hilfe
Fachgebiete
Anästhesiologie Allgemeinmedizin Arbeitsmedizin Augenheilkunde Chirurgie Dermatologie Gynäkologie und Geburtshilfe HNO Innere Medizin Kardiologie Neurologie Onkologie und Hämatologie Orthopädie und Unfallchirurgie Pädiatrie Pathologie Psychiatrie Radiologie Rechtsmedizin Urologie Zahnmedizin
Themen
Typ-2-Diabetes und Adipositas Klimawandel und Gesundheit Neues aus dem Markt COVID-19 Praxis und Beruf Seltene Erkrankungen GOÄ & EBM Panorama
Sammlungen
Kasuistiken Algorithmen & Infografiken Blickdiagnosen Arthropedia FlapFinder (für Dermatochirurgen) Videos Kongressberichterstattung Medizin für Apothekerinnen und Apotheker Für Ärztinnen und Ärzte in Weiterbildung Für Medizinstudierende

Die Highlights vom Kongress des American College of Cardiology 2024

Im April diskutierten die Herz-Kreislauf-Spezialisten aus der ganzen Welt auf dem  Kongress des American College of Cardiology (ACC) u.a. neue Therapieansätze bei akutem Myokardinfarkt, koronarer Herzerkrankung, kardiogenem Schock oder Aortenklappenstenose. In unserem Kongress-Dossier haben wir für Sie Berichte über die „Late-Breaking Trials“ und andere wichtige Studien zusammengestellt. 
Erweiterte Suche
Anmelden
nach oben
Neurotherapeutics
Erschienen in: Neurotherapeutics 3/2022

01.04.2022 | Original Article

Bezafibrate Rescues Mitochondrial Encephalopathy in Mice via Induction of Daily Torpor and Hypometabolic State

verfasst von: Jingwei Lyu, Yuying Zhao, Na Zhang, Xuebi Xu, Rui Zheng, Wenfei Yu, Wang Xin, Chuanzhu Yan, Kunqian Ji

Erschienen in: Neurotherapeutics | Ausgabe 3/2022

Einloggen, um Zugang zu erhalten

Abstract

Leigh syndrome (LS) is one of the most common mitochondrial encephalopathy diseases in infants. To date, there is still an absence of effective therapy. Bezafibrate (BEZ), a pan-peroxisome proliferator-activated receptor (PPAR) agonist, ameliorates the phenotype of the mouse model of mitochondrial disease via an unclear mechanism. Here, we applied it to Ndufs4 knockout (KO) mice, a widely used LS animal model, to observe the therapeutic effects and metabolic changes associated with BEZ treatment to explore the therapeutic strategies for mitochondrial diseases. Administration of BEZ significantly enhances survival and attenuates disease progression in Ndufs4 KO mice. Decreased oxidative stress and stunted growth were also observed. As a PPAR agonist, we did not find mitochondrial biogenesis or enhanced metabolism upon BEZ treatment. On the contrary, mice with dietary BEZ showed daily torpor bouts and lower metabolic rates. We speculate that activating energy-saving metabolism in mice may be associated with the therapeutic effects of BEZ, but the exact mechanism of action requires further study.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
2.
Darin N, Oldfors A, Moslemi AR, Holme E, Tulinius M. The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities. Ann Neurol. 2001;49(3):377–83.PubMedCrossRef
3.
Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39(3):343–51.PubMedCrossRef
4.
Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: one disorder, more than 75 monogenic causes. Ann Neurol. 2016;79(2):190–203.PubMedCrossRef
5.
Lake NJ, Bird MJ, Isohanni P, Paetau A. Leigh syndrome: neuropathology and pathogenesis. J Neuropathol Exp Neurol. 2015;74(6):482–92.PubMedCrossRef
6.
Nagashima T, Mori M, Katayama K, et al. Adult Leigh syndrome with mitochondrial DNA mutation at 8993. Acta Neuropathol. 1999;97(4):416–22.PubMedCrossRef
7.
Han JY, Sung JJ, Park HK, Yoon BN, Lee KW. Adult onset Leigh syndrome with mitochondrial DNA 8344 A>G mutation. J Clin Neurosci. 2014;21(11):2009–11.PubMedCrossRef
8.
Chalmers RM, Lamont PJ, Nelson I, et al. A mitochondrial DNA tRNA(Val) point mutation associated with adult-onset Leigh syndrome. Neurology. 1997;49(2):589–92.PubMedCrossRef
9.
Baertling F, Rodenburg RJ, Schaper J, et al. A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry. 2014;85(3):257–65.PubMedCrossRef
10.
Tenenbaum A, Motro M, Fisman EZ. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. Cardiovasc Diabetol. 2005;4:14.PubMedPubMedCentralCrossRef
11.
Bastin J, Aubey F, Rotig A, Munnich A, Djouadi F. Activation of peroxisome proliferator-activated receptor pathway stimulates the mitochondrial respiratory chain and can correct deficiencies in patients’ cells lacking its components. J Clin Endocrinol Metab. 2008;93(4):1433–41.PubMedCrossRef
12.
Tremblay-Mercier J, Tessier D, Plourde M, et al. Bezafibrate mildly stimulates ketogenesis and fatty acid metabolism in hypertriglyceridemic subjects. J Pharmacol Exp Ther. 2010;334(1):341–6.PubMedCrossRef
13.
Courchesne-Loyer A, St-Pierre V, Hennebelle M, et al. Ketogenic response to cotreatment with bezafibrate and medium chain triacylglycerols in healthy humans. Nutrition. 2015;31(10):1255–9.PubMedCrossRef
14.
Zielinski LP, Smith AC, Smith AG, Robinson AJ. Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling. Mitochondrion. 2016;31:45–55.PubMedPubMedCentralCrossRef
15.
Djouadi F, Bastin J. Species differences in the effects of bezafibrate as a potential treatment of mitochondrial disorders. Cell Metab. 2011;14(6):715–716.
16.
Yatsuga S, Suomalainen A. Effect of bezafibrate treatment on late-onset mitochondrial myopathy in mice. Hum Mol Genet. 2012;21(3):526–35.PubMedCrossRef
17.
Dillon LM, Hida A, Garcia S, Prolla TA, Moraes CT. Long-term bezafibrate treatment improves skin and spleen phenotypes of the mtDNA mutator mouse. PLoS One. 2012;7(9):e44335.
18.
Viscomi C, Bottani E, Civiletto G, et al. In vivo correction of COX deficiency by activation of the AMPK/PGC-1alpha axis. Cell Metab. 2011;14(1):80–90.PubMedPubMedCentralCrossRef
19.
Frambach S, van de Wal MAE, van den Broek PHH, et al. Effects of clofibrate and KH176 on life span and motor function in mitochondrial complex I-deficient mice. Biochim Biophys Acta Mol Basis Dis. 2020;1866(6):165727.
20.
21.
Quintana A, Kruse SE, Kapur RP, Sanz E, Palmiter RD. Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome. Proc Natl Acad Sci U S A. 2010;107(24):10996–1001.PubMedPubMedCentralCrossRef
22.
Kruse SE, Watt WC, Marcinek DJ, et al. Mice with mitochondrial complex I deficiency develop a fatal encephalomyopathy. Cell Metab. 2008;7(4):312–20.PubMedPubMedCentralCrossRef
23.
Leong DW, Komen JC, Hewitt CA, et al. Proteomic and metabolomic analyses of mitochondrial complex I-deficient mouse model generated by spontaneous B2 short interspersed nuclear element (SINE) insertion into NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene. J Biol Chem. 2012;287(24):20652–63.PubMedPubMedCentralCrossRef
24.
Chikahisa S, Tominaga K, Kawai T, et al. Bezafibrate, a peroxisome proliferator-activated receptors agonist, decreases body temperature and enhances electroencephalogram delta-oscillation during sleep in mice. Endocrinology. 2008;149(10):5262–71.PubMedCrossRef
25.
Zhang J, Jia PP, Liu QL, et al. Low ketolytic enzyme levels in tumors predict ketogenic diet responses in cancer cell lines in vitro and in vivo. J Lipid Res. 2018;59(4):625–34.PubMedPubMedCentralCrossRef
26.
Luo Y, Burrington CM, Graff EC, et al. Metabolic phenotype and adipose and liver features in a high-fat Western diet-induced mouse model of obesity-linked NAFLD. Am J Physiol Endocrinol Metab. 2016;310(6):E418–39.PubMedCrossRef
27.
Venegas V, Halberg MC. Measurement of mitochondrial DNA copy number. Methods Mol Biol. 2012;837:327–35.PubMedCrossRef
28.
Ding Q, Tian Y, Wang X, et al. Oxidative damage of tryptophan hydroxylase-2 mediated by peroxisomal superoxide anion radical in brains of mouse with depression. J Am Chem Soc. 2020;142(49):20735–43.PubMedCrossRef
29.
30.
Johnson SC, Yanos ME, Kayser EB, et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science. 2013;342(6165):1524–8.PubMedPubMedCentralCrossRef
31.
Johri A, Calingasan NY, Hennessey TM, et al. Pharmacologic activation of mitochondrial biogenesis exerts widespread beneficial effects in a transgenic mouse model of Huntington’s disease. Hum Mol Genet. 2012;21(5):1124–37.PubMedCrossRef
32.
Dumont M, Stack C, Elipenahli C, et al. Bezafibrate administration improves behavioral deficits and tau pathology in P301S mice. Hum Mol Genet. 2012;21(23):5091–105.PubMedPubMedCentralCrossRef
33.
Lisa P, Chu SJS. Oral bezafibrate induces daily torpor and FGF21 in mice in a PPAR alpha dependent manner. J Therm Biol. 2012;37(4):291–6.CrossRef
34.
35.
Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis. 2007;12(5):913–22.PubMedCrossRef
36.
Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem. 1972;247(10):3170–5.PubMedCrossRef
37.
Kim T, Yang Q. Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system. World J Cardiol. 2013;5(6):164–74.PubMedPubMedCentralCrossRef
38.
Suomalainen A, Elo JM, Pietilainen KH, et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol. 2011;10(9):806–18.PubMedPubMedCentralCrossRef
39.
Davis RL, Liang C, Edema-Hildebrand F, et al. Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology. 2013;81(21):1819–26.PubMedCrossRef
40.
Ji X, Zhao L, Ji K, et al. Growth differentiation factor 15 is a novel diagnostic biomarker of mitochondrial diseases. Mol Neurobiol. 2017;54(10):8110–6.PubMedCrossRef
41.
LeRoith D, Yakar S. Mechanisms of disease: metabolic effects of growth hormone and insulin-like growth factor 1. Nat Clin Pract Endocrinol Metab. 2007;3(3):302–10.PubMedCrossRef
42.
Underwood LE, Thissen JP, Lemozy S, Ketelslegers JM, Clemmons DR. Hormonal and nutritional regulation of IGF-I and its binding proteins. Horm Res. 1994;42(4–5):145–51.PubMedCrossRef
43.
Silha JV, Murphy LJ. Insights from insulin-like growth factor binding protein transgenic mice. Endocrinology. 2002;143(10):3711–4.PubMedCrossRef
44.
Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res. 1996;37(5):907–25.PubMedCrossRef
45.
Maki KC. Fibrates for treatment of the metabolic syndrome. Curr Atheroscler Rep. 2004;6(1):45–51.PubMedCrossRef
46.
47.
Milder J, Patel M. Modulation of oxidative stress and mitochondrial function by the ketogenic diet. Epilepsy Res. 2012;100(3):295–303.PubMedCrossRef
48.
Wall CE, Whyte J, Suh JM, et al. High-fat diet and FGF21 cooperatively promote aerobic thermogenesis in mtDNA mutator mice. Proc Natl Acad Sci U S A. 2015;112(28):8714–9.PubMedPubMedCentralCrossRef
49.
Srivastava S, Diaz F, Iommarini L, et al. PGC-1alpha/beta induced expression partially compensates for respiratory chain defects in cells from patients with mitochondrial disorders. Hum Mol Genet. 2009;18(10):1805–12.PubMedPubMedCentralCrossRef
50.
Casarin A, Giorgi G, Pertegato V, et al. Copper and bezafibrate cooperate to rescue cytochrome c oxidase deficiency in cells of patients with SCO2 mutations. Orphanet J Rare Dis. 2012;7:21.PubMedPubMedCentralCrossRef
51.
Grings M, Moura AP, Parmeggiani B, et al. Bezafibrate prevents mitochondrial dysfunction, antioxidant system disturbance, glial reactivity and neuronal damage induced by sulfite administration in striatum of rats: implications for a possible therapeutic strategy for sulfite oxidase deficiency. Biochim Biophys Acta Mol Basis Dis. 2017;1863(9):2135–48.PubMedCrossRef
52.
53.
Swoap SJ, Gutilla MJ. Cardiovascular changes during daily torpor in the laboratory mouse. Am J Physiol Regul Integr Comp Physiol. 2009;297(3):R769–74.PubMedPubMedCentralCrossRef
54.
Heldmaier G, Ortmann S, Elvert R. Natural hypometabolism during hibernation and daily torpor in mammals. Respir Physiol Neurobiol. 2004;141(3):317–29.PubMedCrossRef
55.
Parmeggiani B, Grings M, da Rosa-Junior NT, et al. Bezafibrate prevents glycine-induced increase of antioxidant enzyme activities in rat striatum. Mol Neurobiol. 2019;56(1):29–38.PubMedCrossRef
56.
Ishida N. Role of PPARα in the control of torpor through FGF21-NPY pathway: From circadian clock to seasonal change in mammals. PPAR Res. 2009;412949.
57.
Fisher FM, Maratos-Flier E. Understanding the physiology of FGF21. Annu Rev Physiol. 2016;78:223–41.PubMedCrossRef
58.
Gälman C, Lundåsen T, Kharitonenkov A, et al. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell Metab. 2008;8(2):169–74.PubMedCrossRef
59.
Steele H, Gomez-Duran A, Pyle A, et al. Metabolic effects of bezafibrate in mitochondrial disease. EMBO Mol Med. 2020;12(3):e11589.
60.
Mullican SE, Lin-Schmidt X, Chin CN, et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017;23(10):1150–7.PubMedCrossRef
61.
Emmerson PJ, Wang F, Du Y, et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med. 2017;23(10):1215–9.PubMedCrossRef
62.
Yang L, Chang CC, Sun Z, et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med. 2017;23(10):1158–66.PubMedCrossRef
63.
Branco AF, Ferreira A, Simoes RF, et al. Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur J Clin Invest. 2016;46(3):285–98.PubMedCrossRef
64.
65.
Felici R, Cavone L, Lapucci A, et al. PARP inhibition delays progression of mitochondrial encephalopathy in mice. Neurotherapeutics. 2014;11(3):651–64.PubMedPubMedCentralCrossRef
66.
Metadaten
Titel
Bezafibrate Rescues Mitochondrial Encephalopathy in Mice via Induction of Daily Torpor and Hypometabolic State
verfasst von
Jingwei Lyu
Yuying Zhao
Na Zhang
Xuebi Xu
Rui Zheng
Wenfei Yu
Wang Xin
Chuanzhu Yan
Kunqian Ji
Publikationsdatum
01.04.2022
Verlag
Springer International Publishing
Erschienen in
Neurotherapeutics / Ausgabe 3/2022
Print ISSN: 1933-7213
Elektronische ISSN: 1878-7479
DOI
https://doi.org/10.1007/s13311-022-01216-9

Weitere Artikel der Ausgabe 3/2022

Neurotherapeutics 3/2022 Zur Ausgabe

Review

Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies

Review

Evolution of Anti-B Cell Therapeutics in Autoimmune Neurological Diseases

Original Article

AAV-Mediated Artificial miRNA Reduces Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models

Original Article

Low-Dose Ziprasidone in Combination with Sertraline for First-Episode Drug-Naïve Patients with Schizophrenia: a Randomized Controlled Trial

Review

The Role of the Complement System in Chronic Inflammatory Demyelinating Polyneuropathy: Implications for Complement-Targeted Therapies

Review

Monoclonal Antibodies in the Treatment of Relapsing Multiple Sclerosis: an Overview with Emphasis on Pregnancy, Vaccination, and Risk Management

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Kostenlos registrieren

Neu im Fachgebiet Neurologie

Hirnblutung unter DOAK und VKA ähnlich bedrohlich

17.05.2024 Direkte orale Antikoagulanzien Nachrichten

Kommt es zu einer nichttraumatischen Hirnblutung, spielt es keine große Rolle, ob die Betroffenen zuvor direkt wirksame orale Antikoagulanzien oder Marcumar bekommen haben: Die Prognose ist ähnlich schlecht.

Thrombektomie auch bei großen Infarkten von Vorteil

16.05.2024 Ischämischer Schlaganfall Nachrichten

Auch ein sehr ausgedehnter ischämischer Schlaganfall scheint an sich kein Grund zu sein, von einer mechanischen Thrombektomie abzusehen. Dafür spricht die LASTE-Studie, an der Patienten und Patientinnen mit einem ASPECTS von maximal 5 beteiligt waren.

Schwindelursache: Massagepistole lässt Otholiten tanzen

14.05.2024 Benigner Lagerungsschwindel Nachrichten

Wenn jüngere Menschen über ständig rezidivierenden Lagerungsschwindel klagen, könnte eine Massagepistole der Auslöser sein. In JAMA Otolaryngology warnt ein Team vor der Anwendung hochpotenter Geräte im Bereich des Nackens.

Schützt Olivenöl vor dem Tod durch Demenz?

10.05.2024 Morbus Alzheimer Nachrichten

Konsumieren Menschen täglich 7 Gramm Olivenöl, ist ihr Risiko, an einer Demenz zu sterben, um mehr als ein Viertel reduziert – und dies weitgehend unabhängig von ihrer sonstigen Ernährung. Dafür sprechen Auswertungen zweier großer US-Studien.

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen
Bildnachweise