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

Bitto, A.; Grillo, A. S.; Stanaway, I. B.; Nguyen, B. M. G.; Ying, K.; Tung, H.; Smith, K.; Tran, N.; Velikanje, G.; Urfer, S.; Snyder, J. M.; Kayser, E.-B.; Wang, L.; Smith, D. L.; Thompson, J. W.; Dubois, L.; DePaolo, W.; Kaeberlein, M.

doi:10.1101/2022.01.31.478591

bioRxiv · 10.1101/2022.01.31.478591

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

Bitto, A.·Grillo, A. S.·Stanaway, I. B.·Nguyen, B. M. G.·Ying, K.·Tung, H.·Smith, K.·Tran, N.·Velikanje, G.·Urfer, S.·Snyder, J. M.·Kayser, E.-B.·Wang, L.·Smith, D. L.·Thompson, J. W.·Dubois, L.·DePaolo, W.·Kaeberlein, M.

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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 aging process. Rapamycin, a drug that increases lifespan and health during normative aging 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 aging in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of mTOR inhibition. 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. This study provides the first evidence that alteration of the gut microbiome may impact severe mitochondrial disease and provides further support for the model that biological aging and severe mitochondrial disorders share underlying common mechanisms.

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Bitto, A., Grillo, A. S., Stanaway, I. B., Nguyen, B. M. G., Ying, K., Tung, H., Smith, K., Tran, N., Velikanje, G., Urfer, S., Snyder, J. M., Kayser, E.-B., Wang, L., Smith, D. L., Thompson, J. W., Dubois, L., DePaolo, W., Kaeberlein, M.. 2022-02-01. Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh Syndrome. https://doi.org/10.1101/2022.01.31.478591

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