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

Nature Metabolism volume 5, pages 955–967 (2023)Cite this article

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Abstract

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.

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Fig. 1: Acarbose reduces brain lesions across the brain in Ndufs4−/− mice.
Fig. 2: Acarbose increases survival and delays onset of disease in Ndufs4−/− mice.
Fig. 3: Acarbose remodels the microbiome and its metabolism in Ndufs4−/− mice.
Fig. 4: SCFAs recapitulate the effects of acarbose.

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Data availability

The data used to generate the figures in this manuscript are publicly available and published along with the paper. Further information and requests for resources and reagents should be directed to and will be fulfilled by Alessandro Bitto (ab62@uw.edu). Source data are provided with this paper.

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Acknowledgements

We acknowledge funding from the Nathan Shock Center of Excellence for the Biology of Aging (grant no. 3 P30 AG 013280) and from grant no. 1 R01 NS98329 Mechanisms of Mitochondrial Disease Suppression in Ndufs4 Knockout Mice.

Author information

Author notes

  1. Takashi K. Ito

    Present address: RIKEN Center for Sustainable Resource Science, Saitama, Japan

Authors and Affiliations

  1. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

    Alessandro Bitto, Anthony S. Grillo, Takashi K. Ito, Bao M. G. Nguyen, Ngoc Tran, Gunnar Velikanje, Silvan R. Urfer, Jacob Barton, Ayush Sharma & Matt Kaeberlein

  2. Division of Nephrology, School of Medicine, University of Washington, Seattle, WA, USA

    Ian B. Stanaway

  3. Harborview Medical Center, Kidney Research Institute, Seattle, WA, USA

    Ian B. Stanaway

  4. T.H. Chan School of Public Health, Harvard University, Boston, MA, USA

    Kejun Ying

  5. Shape Therapeutics, Seattle, WA, USA

    Herman Tung

  6. Seattle Genetics, Seattle, WA, USA

    Kaleb Smith

  7. Department of Comparative Medicine, University of Washington, Seattle, WA, USA

    Jessica M. Snyder

  8. Seattle Children’s Research Institute, Seattle, WA, USA

    Ernst-Bernhard Kayser

  9. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA

    Lu Wang

  10. Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA

    Daniel L. Smith Jr.

  11. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA

    J. Will Thompson

  12. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA

    Laura DuBois

  13. Department of Microbiology, University of Washington, Seattle, WA, USA

    William DePaolo

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  1. Alessandro Bitto
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Contributions

A.B. and M.K. devised the study. A.B., A.S.G., B.M.G.N., H.T., K.S., N.T.,G.V., J.B. and A.S. administered treatments, collected weight data and scored neurological phenotypes and survival. A.B., H.T., K.S., A.S. and N.T. collected tissues and ran western blot analyses. A.B., A.S.G., B.M.G.N., H.T., K.S., N.T., G.V. and S.R.U. helped maintain the mouse colony and genotyped animals. I.B.S. and W.D. helped with the design, execution and analysis of microbiome sequencing data. K.Y. and L.W. helped with the analysis of metabolomics data. E.-B.K. helped with the design and collection of samples for metabolomics analysis. J.M.S. performed all histopathology scoring. D.L.S. Jr. contributed acarbose and scientific rationale for the study. J.W.T. and L.D. measured the abundance of SCFAs. T.K.I. measured survival and neurological symptoms onset in mice treated with antibiotics. A.B. and M.K. wrote the manuscript.

Corresponding author

Correspondence to Matt Kaeberlein.

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Nature Metabolism thanks Albert Quintana and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt, in collaboration with the Nature Metabolism team.

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Extended data

Extended Data Fig. 1 Acarbose reduces brain inflammation in Ndufs4−/− mice.

(a) Semi-quantitative immunohistochemistry for GFAP (b) and Iba1 (c) in several brain regions. Data are presented as individual values (closed circles wild type untreated, closed triangles Ndufs4−/− untreated, open triangles Ndufs4−/− acarbose-treated), superimposed on mean +/− standard deviation. Mixed-Effect Model p-values; GFAP; wild type untreated vs Ndufs4−/− untreated =0.0003 (mean difference −1.333, 95% CI −1.992 to −0.6751), Striatum =0.0088 (mean difference = −0.7333, 95% CI −1.282 to −0.1851), Thalamus/Hippocampus =0.0002 (mean difference = −0.9167, 95% CI −1.387 to −0.4461), Cerebellum/Brainstem =0.0001 (mean difference −1.283, 95% CI −1.907 to −0.6598), Ndufs4−/− untreated vs. Ndufs4−/− acarbose-treated, olfactory bulb = 0.0026 (mean difference =1.3, 95% CI interval 0.4992 to 2.101), Thalamus/Hippocampus =0.0378 (mean difference =0.75, 95% CI 0.04374 to 1.456), cerebellum/brainstem, <0.0001 (mean difference =1.557, 95% CI 1.013 to 2.101); Iba1; wild type untreated vs Ndufs4−/− untreated, olfactory bulb <0.0001 (mean difference −1.75, −2.223 to −1.277), striatum =0.0303 (mean difference −0.5333, 95% CI −1.019 to −0.0475), Thalamus/Hippocampus =0.0307 (mean difference =−0.5833, 95% CI −1.117 to −0.04932), cerebellum =0.0134 (mean difference −0.8182, 95% CI −1.473 to −0.1630), cerebellum/brainstem =0.0003 (mean difference =−1.038, 95% CI −1.584 to −0.4916), wild type untreated vs Ndufs4−/− acarbose-treated, thalamus/hippocampus =0.0031 (mean difference =−0.9167, 95% CI −1.488 to −0.3457). N = 12/group wild type and Ndufs4−/− untreated, N = 7 Ndufs4−/− acarbose-treated. d. Western blot and e. densitometric analysis of Trem-2 expression in 50 days old brain lysates from wild type untreated (dark blue), Ndufs4−/− untreated (light blue), and acarbose-treated Ndufs4−/− mice (red). Bars are mean +/− standard deviation. N = 4/group, One-way ANOVA.

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Extended Data Fig. 2 Acarbose effects are independent of sex.

A. and B. Individual survival curves of control-chow and acarbose-chow fed Ndufs4−/− mice. A. Log-rank p < 0.0001 N = 13/group B. Log-rank p < 0.001 N = 13 untreated, N = 12 acarbose-treated C. Pooled lifespan curves divided by sex. Log-rank p < 0.5944, N = 14 acarbose-treated males, N = 11 acarbose-treated females. D. Weight progression from weaning until post-natal day 81. Solid dark blue: female wild type mice fed control chow. Dotted dark blue: male wild type mice fed control chow. Solid dark red: female wild type mice fed acarbose chow. Dotted dark red: male wild type mice fed acarbose chow. Solid light blue: female Ndufs4−/− mice fed control chow Dotted light blue: male Ndufs4−/− mice fed control chow. Solid light red: female Ndufs4−/− mice fed acarbose chow. Dotted light red: male Ndufs4−/− mice fed acarbose chow. N = 8 female wild type untreated, N = 9 male wild type untreated, N = 5 females Ndufs4−/− untreated, N = 7 males Ndufs4−/− untreated, N = 4 females wild type acarbose, N = 4 males wild type acarbose, N = 7 females Ndufs4−/− acarbose, N = 6 males Ndufs4−/− acarbose. E. Comparison of weights at 35 days post-natal for control-chow fed wild type, Ndufs4−/− mice, acarbose-chow fed wild type, and Ndufs4−/− mice, divided by sex. *** p < 0.001 one way ANOVA. N = 8 female wild type untreated, N = 9 male wild type untreated, N = 5 females Ndufs4−/− untreated, N = 7 males Ndufs4−/− untreated, N = 4 females wild type acarbose, N = 4 males wild type acarbose, N = 7 females Ndufs4−/− acarbose, N = 6 males Ndufs4−/− acarbose.

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Extended Data Fig. 3 Acarbose does not inhibit mTORc1 signaling but does not further extend lifespan in Ndufs4−/− mice treated with rapamycin.

a. Western blots of ribosomal protein S6 phosphorylation at serine 235/236. b. c. Densitometric analysis of the western blots in panel A. Data are mean +/− standard deviation. One-way ANOVA adjusted p-values: wild type untreated vs. wild type rapamycin =0.0148 (mean difference =1.813, 95% CI 0.3369 to 3.289), Ndufs4−/− untreated vs Ndufs4−/− rapamycin treated =0.0092 (mean difference= 2.048. 95% CI 0.4927 to 3.604). N = 4 wild type and Ndufs4−/− untreated, N = 5 wild type and Ndufs4−/− acarbose or rapamycin treated. d. Onset of neurological symptoms (clasping) measured in days after birth in control-chow (blue,) 0.1% acarbose-chow (red) fed, 8 mg/kg/day I.P. rapamycin-treated (green,) acarbose-chow fed and every other day rapamycin treated (orange) Ndufs4−/− mice. Data are mean +/− standard deviation. One-way ANOVA adjusted p-values: Ndufs4−/− untreated vs acarbose-treated =0.0005 (mean difference −12.32, 95% CI −19.97 to −4.667), Ndufs4−/− untreated vs. rapamycin-treated =0.0186 (mean difference =−9.071, 95% CI −16.98 to −1.163), Ndufs4−/− untreated vs double-treated <0.0001 (mean difference = −19.85, 95% CI −27.50 to −12.20), acarbose-treated Ndufs4−/− vs double treated =0.0375 (mean difference =−7.533, 95% CI −14.75 to −0.3207), rapamycin-treated Ndufs4−/− vs double treated =0.0020 (mean difference =−10.78, 95% CI −18.26 to −3.295). N = 12 Ndufs4−/− untreated, N = 15 Ndufs4−/− acarbose, N = 13 Ndufs4−/− rapamycin, N = 15 Ndufs4−/− double treated e. Survival curves of Ndufs4−/− mice fed either control (blue,) 0.1% acarbose diet (red,) treated with 8 mg/kg daily intraperitoneal rapamycin (orange,) acarbose diet + every other day rapamycin (orange). Median lifespan was 52 days for control-chow fed, 76.5 days for acarbose-chow fed mice (log-rank p < 0.05), 80 for rapamycin treated mice (log-rank p < 0.05), and 74 for double treatment regimens (log-rank p < 0.01). Double treatment with acarbose and every other day rapamycin also increased maximum lifespan, Mann-Whitney U, p < 0.05. N = 13 Ndufs4−/− untreated, N = 12 Ndufs4−/− acarbose, N = 16 Ndufs4−/− rapamycin, N = 15 Ndufs4−/− double treated f. Comparison of body weight progression at 35 days post-natal for untreated wt (dark blue), untreated Ndufs4−/− (light blue), acarbose treated wt (dark red), acarbose treated Ndufs4−/− (light red), rapamycin treated wt (dark green), rapamycin treated Ndufs4−/− (light green), double treated wt (dark orange), and double treated Ndufs4−/− mice (light orange). One-way ANOVA adjusted p-values: wild type untreated vs Ndufs4−/− untreated <0.0001 (mean difference =4.958, 95% CI 2.436 to 7.480), Ndufs4−/− untreated vs rapamycin-treated =0.0029 (mean difference =2.880, 95% CI 0.6592 to 5.101), Ndufs4−/− untreated vs double-treated =0.0119 (mean difference = 2.604, 95% CI 0.3549 to 4.853), acarbose-treated Ndufs4−/− vs rapamycin-treated =0.0229 (mean difference =2.199. 95% CI 0.1792 to 4.220). N = 10 wild type untreated, N = 13 Ndufs4−/− untreated, N = 11 wild type acarbose-treated, N = 17 Ndufs4−/− acarbose-treated, N = 9 wild type rapamycin-treated, N = 16 Ndufs4−/− rapamycin-treated, N = 10 wild type double treated, N = 15 Ndufs4−/− double treated, sex: both. G. Weight progression from weaning until post-natal day 81. Solid dark blue: wild type mice fed control chow. Solid dark red: wild type mice fed acarbose chow. Dotted light blue: Ndufs4−/− mice fed control chow. Dotted light red: Ndufs4−/− mice fed acarbose chow. Solid dark green: wt rapamycin. Dotted light green: Ndufs4−/− rapamycin. Solid dark orange: wt double treated. Dotted light orange: Ndufs4−/− double treated. N = 10 wild type untreated, N = 13 Ndufs4−/− untreated, N = 11 wild type acarbose-treated, N = 17 Ndufs4−/− acarbose-treated, N = 9 wild type rapamycin-treated, N = 16 Ndufs4−/− rapamycin-treated, N = 10 wild type double treated, N = 15 Ndufs4−/− double treated, sex: both.

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Extended Data Fig. 4 Combination therapy with acarbose and rapamycin in Ndufs4−/− mice.

A. Western blot and B. densitometric analysis of ribosomal protein S6 phosphorylation in brains from 50 days old wild type untreated, Ndufs4−/− untreated, and acarbose treated Ndufs4−/− mice. Data are mean +/− standard deviation N = 4/group, One-way ANOVA. C. Daily double treatment with acarbose and rapamycin prevents growth and ultimately causes death in newly weaned mice. Solid lines indicate weight progression individual animals on daily double treatment with rapamycin and acarbose from weaning. Dark orange squares: wild type animals, light orange triangles: Ndufs4−/− animals Dotted lines are average weights of untreated animals, dark blue squares: wild type untreated, light blue triangles, Ndufs4−/− untreated. D. Onset of neurological symptoms (clasping) measured in days after birth in control-chow (blue,) 0.1% acarbose-chow (red) fed, 8 mg/kg/day I.P. rapamycin-treated (green,) acarbose-chow fed from weaning and daily rapamycin treated from post natal (p.n.) day 28 (grey) Ndufs4−/− mice. Data are mean +/− standard deviation. One-way ANOVA adjusted p-values: Ndufs4−/− untreated vs acarbose-treated =0.0004 (mean difference −12.32, 95% CI −20.08 to −4.550), Ndufs4−/− untreated vs. rapamycin-treated =0.0196 (mean difference =−9.071, 95% CI −17.10 to −10.43), Ndufs4−/− untreated vs double-treated <0.0001 (mean difference = −21.28, 95% CI −29.65 to −12.91), acarbose-treated Ndufs4−/− vs double treated =0.0202 (mean difference =−8.964, 95% CI −16.92 to −1.004), rapamycin-treated Ndufs4−/− vs double treated =0.0011 (mean difference =−12.21, 95% CI −20.42 to −3.995). N = 12 Ndufs4−/− untreated, N = 15 Ndufs4−/− acarbose, N = 13 Ndufs4−/− rapamycin, N = 11 Ndufs4−/− double treated. E. Survival curves of Ndufs4-/- mice fed either control (blue), 0.1% acarbose diet (red), treated with 8 mg/kg daily intraperitoneal rapamycin (orange), acarbose diet + every other day rapamycin (orange). Median lifespan was 52 days for control-chow fed, 76.5 days for acarbose-chow fed mice (log-rank p < 0.05), 80 for rapamycin treated mice (log-rank p < 0.05), and 74 for double treatment regimens (log-rank p < 0.01). Double treatment with acarbose and every other day rapamycin also increased maximum lifespan, Mann-Whitney U, p < 0.05. N = 13 Ndufs4-/- untreated, N = 12 Ndufs4-/- acarbose, N = 16 Ndufs4-/- rapamycin, N = 15 Ndufs4-/- double treated F. Comparison of body weight progression at 35 days post-natal for untreated wt (dark blue), untreated Ndufs4-/- (light blue), acarbose treated wt (dark red), acarbose treated Ndufs4-/- (light red), rapamycin treated wt (dark green), rapamycin treated Ndufs4-/- (light green), double treated wt (dark orange), and double treated Ndufs4-/- mice (light orange). One-way ANOVA adjusted p-values: wild type untreated vs Ndufs4-/- untreated <0.0001 (mean difference = 4.958, 95% CI 2.436 to 7.480), Ndufs4-/- untreated vs rapamycin-treated = 0.0029 (mean difference = 2.880, 95% CI 0.6592 to 5.101), Ndufs4-/- untreated vs double-treated = 0.0119 (mean difference = 2.604, 95% CI 0.3549 to 4.853), acarbose-treated Ndufs4-/- vs rapamycin-treated = 0.0229 (mean difference = 2.199. 95% CI 0.1792 to 4.220). N = 10 wild type untreated, N = 13 Ndufs4-/- untreated, N = 11 wild type acarbose-treated, N = 17 Ndufs4-/- acarbose-treated, N = 9 wild type rapamycin-treated, N = 16 Ndufs4-/- rapamycin-treated, N = 10 wild type double treated, N = 15 Ndufs4-/- double treated, sex: both. G. Weight progression from weaning until post-natal day 81. Solid dark blue: wild type mice fed control chow. Solid dark red: wild type mice fed acarbose chow. Dotted light blue: Ndufs4-/- mice fed control chow. Dotted light red: Ndufs4-/- mice fed acarbose chow. Solid dark green: wt rapamycin. Dotted light green: Ndufs4-/- rapamycin. Solid dark orange: wt double treated. Dotted light orange: Ndufs4-/- double treated. N = 10 wild type untreated, N = 13 Ndufs4-/- untreated, N = 11 wild type acarbose-treated, N = 17 Ndufs4-/- acarbose-treated, N = 9 wild type rapamycin-treated, N = 16 Ndufs4-/- rapamycin-treated, N = 10 wild type double treated, N = 15 Ndufs4-/- double treated, sex: both.

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Extended Data Fig. 5 Metabolic profiling of brain regions in Ndufs4−/− mice treated with acarbose.

a. Schematic diagram of the metabolomics assay. b. Volcano plot of metabolic features in the olfactory bulb of untreated Ndufs4−/− mice compared to wild type littermates. Red dots are significantly altered metabolites. Linear model adjusted p-value (Benjamini-Hochberg FDR correction) <0.05. Individual metabolites p-values available in metabolomics dataset. c. Heat map of the relative abundance of selected significantly altered metabolites in the olfactory bulb of wild type untreated (WT-U), Ndufs4−/− untreated (KO-U), and acarbose-treated Ndufs4−/− mice (KO-A). d. and e. Specific Pathway Analysis of glycolysis intermediates in the olfactory bulb of untreated (D.) and acarbose-treated (E.) Ndufs4−/− mice. Red metabolites are significantly more abundant compared to untreated wild type; blue metabolites are significantly less abundant. Linear model adjusted p-value (Benjamini-Hochberg FDR correction) <0.05. Individual metabolites p-values available in metabolomics dataset. N = 4-5 per group.

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Extended Data Fig. 6 Metabolomics reveals glucose dishomeostasis in Ndufs4−/− brains.

a Principal component analysis of the metabolomics dataset described in Fig. 4a. Light blue squares and circles, wild type untreated; red squares and circles, Ndufs4−/− untreated; dark blue squares and circles, acarbose-treated Ndufs4−/−. b. Metabolites Set Enrichment Analysis (MSEA) of metabolic pathways enriched in the olfactory bulb of untreated Ndufs4−/− compared to wild type animals. c. Metabolites Pathway Analysis (MPA) of metabolic pathways enriched in the olfactory bulb of untreated Ndufs4−/− compared to wild type animals. Color denotes p-value, same scale as in panel B., size of circles denotes impact. N = 4-5 per group for panels A to C. d. 1 h post-prandial blood glucose levels in wild type and Ndufs4−/− mice untreated or treated with acarbose. Data are mean +/− standard deviation. One-way ANOVA adjusted p-values: wild type untreated vs. Ndufs4−/− untreated =0.0018 (mean difference= 51.6, 95% CI 17.64 to 85.56), wild type untreated vs wild type acarbose =0.0428 (mean difference =30.2, 95% CI 0.7883 to 59.61). N = 5 wild type and Ndufs4−/− untreated, N = 10 wild type N = 13 Ndufs4−/− acarbose-treated. e. Survival plot of Ndufs4−/− mice treated with 0.2%, 0.4% 2-deoxyglucose (2DG) or 1%, 10% glucosamine (GlcN) mixed in the food. N = 26 untreated, N = 9 0.2% 2-deoxyglucose, N = 11 0.4% 2-deoxyglucose, N = 25 1% glucosamine, N = 13 10% glucosamine. F. Onset of clasping in Ndufs4−/− mice treated with 2-deoxyglucose (2DG) or glucosamine (GlcN). Data are mean +/− standard deviation. N = 12 untreated, N = 9 0.2% and 0.4% deoxyglucose, N = 21 1% glucosamine, N = 8 10% glucosamine.

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Extended Data Fig. 7 Acarbose alters the intestinal microbiome in Ndufs4−/− mice.

a. Centered log-ratio normalized proportion of Bacteroides divided by genotype and treatment. Linear regression p-value by treatment adjusted by genotype =0.001. N = 9-11 per group b-e. Center log-ratio normalized proportion of Prevotella (B.) Alistipes (C.) Clostridium (D.) and Rikenella (E.) divided by treatment. Linear regression p-value by treatment= 0.023 (B), 0.026 (C), 0.036 (D), 0.038 (E), FDR = 0.136.

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Extended Data Fig. 8 Tributyrin supplementation improves survival in Ndufs4−/− mice.

a. Survival plot of Ndufs4−/− treated with 50 mg/kg or 100 g/kg tributyrin. N = 25 untreated, N = 12 50 g/kg tributyrin, N = 16 100 g/kg tributyrin. b. Weight progression from weaning until post-natal day 81. Solid dark blue: wild type mice fed control chow (dark blue), Ndufs4−/− untreated (light blue), and tributyrin (shades of brown). Data are mean +/− standard deviation. N = 13 wild type and Ndufs4−/− untreated, N = 12 wild type 10 g/kg tributyrin, N = 18 Ndufs4−/− 10 g/kg tributyrin, N = 13 wild type and Ndufs4−/− 50 g/kg tributyrin, N = 12 wild type 100 g/kg tributyrin, N = 15 100 g/kg tributyrin. N = 20/group c-d. Linear trend of Ndufs4−/− (C.) and wild type mice (D.) weight after treatment with increasing doses of tributyrin at post-natal day 35. Data are mean +/− standard deviation. One-way ANOVA test for linear trend p-value = 0.0003 (Ndufs4−/−), 0.0005 (wild type). N = 13 wild type and Ndufs4−/− untreated, N = 12 wild type 10 g/kg tributyrin, N = 18 Ndufs4−/− 10 g/kg tributyrin, N = 13 wild type and Ndufs4−/− 50 g/kg tributyrin, N = 12 wild type 100 g/kg tributyrin, N = 15 100 g/kg tributyrin. e. Weight progression from weaning until post-natal day 70. Solid: wild type mice, dotted: Ndufs4−/− mice fed control chow (blue), tributyrin (brown), or rapamycin (green). Data are mean +/− standard deviation. f. Comparison of weights at 35 days post-natal for wild type and Ndufs4−/− fed either chow (blue), chow supplemented with 10 g/kg tributyrin (brown), injected with rapamycin (green), or fed chow supplemented with 10 g/kg tributyrin and injected with rapamycin (orange). Data are mean +/− standard deviation. One-way ANOVA, adjusted p-values: wt untreated vs Ndufs4−/− untreated =0.0112 (mean difference 4.5, 95% CI 0.8824 to 8.119), Ndufs4−/− untreated vs. Ndufs4−/− rapamycin-treated <0.0001 (mean difference 3.533, 95% CI 1.807 to 5.260), Ndufs4−/− untreated vs Ndufs4−/− tributyrin+rapamycin-treated =0.007 (mean difference 2.330, 95% CI 0.4753 to 4.184). N = 11 wild type untreated, N = 21 Ndufs4−/− untreated, N = 12 wild type 10 g/kg tributyrin, N = 18 Ndufs4−/− 10 g/kg tributyrin, N = 9 wt rapamycin, N = 17 Ndufs4−/− rapamycin, N = 7 wt tributyrin + rapamycin, N = 13 Ndufs4−/− tributyrin + rapamycin. g. Onset of clasping in untreated (blue), tributyrin-treated (brown), rapamycin treated (green), or tributyrin and rapamycin-treated Ndufs4−/− mice. Data are mean +/− standard deviation. One-way ANOVA, adjusted p-value untreated vs tributyrin =0.0486 (mean difference −5.888, 95% CI −11.75 to −0.02388), untreated vs. rapamycin =0.0126 (mean difference =−7.354, 95% CI −13.54 to −1.172), untreated vs. tributyrin+rapamycin <0.0001 (mean difference = −11.43, 95% CI −17.61 to −5.248). N = 15 untreated, N = 16 tributyrin-treated, N = 13 rapamycin-treated, N = 13 tributyrin and rapamycin treated. h. Survival plot of Ndufs4-/- untreated (blue), tributyrin-treated (brown), rapamycin treated (green), or tributyrin and rapamycin-treated Ndufs4-/- mice. N = 12 untreated, N = 18 tributyrin, N = 16 rapamycin, N = 13 tributyrin + rapamycin. Log-rank p<0.0001.

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Extended Data Table 1 Short-Chain Fatty Acids Panel
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Western blot scans and source data tables.

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Bitto, A., Grillo, A.S., Ito, T.K. et al. Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome. Nat Metab 5, 955–967 (2023). https://doi.org/10.1038/s42255-023-00815-w

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