Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.

Autor: Bitto A; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Grillo AS; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Ito TK; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.; RIKEN Center for Sustainable Resource Science, Saitama, Japan., Stanaway IB; Division of Nephrology, School of Medicine, University of Washington, Seattle, WA, USA.; Harborview Medical Center, Kidney Research Institute, Seattle, WA, USA., Nguyen BMG; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Ying K; T.H. Chan School of Public Health, Harvard University, Boston, MA, USA., Tung H; Shape Therapeutics, Seattle, WA, USA., Smith K; Seattle Genetics, Seattle, WA, USA., Tran N; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Velikanje G; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Urfer SR; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Snyder JM; Department of Comparative Medicine, University of Washington, Seattle, WA, USA., Barton J; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Sharma A; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., Kayser EB; Seattle Children's Research Institute, Seattle, WA, USA., Wang L; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA., Smith DL Jr; Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA., Thompson JW; Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA., DuBois L; Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA., DePaolo W; Department of Microbiology, University of Washington, Seattle, WA, USA., Kaeberlein M; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. kaeber@uw.edu.
Jazyk: angličtina
Zdroj: Nature metabolism [Nat Metab] 2023 Jun; Vol. 5 (6), pp. 955-967. Date of Electronic Publication: 2023 Jun 26.
DOI: 10.1038/s42255-023-00815-w
Abstrakt: Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout (Ndufs4 -/- ) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh syndrome. Here we show that another drug that extends lifespan and delays normative ageing in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4 -/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of inhibition of the mechanistic target of rapamycin. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4 -/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short-chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression, while depletion of the endogenous microbiome in Ndufs4 -/- mice appears to fully recapitulate the effects of acarbose on healthspan and lifespan in these animals. To our knowledge, this study provides the first evidence that alteration of the gut microbiome plays a significant role in severe mitochondrial disease and provides further support for the model that biological ageing and severe mitochondrial disorders share underlying common mechanisms.
(© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Databáze: MEDLINE
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