Butyrate extends health and lifespan in mice with mitochondrial deficiency
Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. To investigate novel strategies that alleviate mitochondrial dysfunction, we have generated an ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - <i>Tfam</i> <sup>fl/fl</sup> <i>Ub</i> <sup>Cre-ERT2</sup> (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share deficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of <i>Tfam</i> deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.
Authors
- Carolina Simó (ORCID: https://orcid.org/0000-0002-7140-0795)
- G. Soto-Heredero
- Garcia-Canas Virginia
- Elisa Carrasco (ORCID: https://orcid.org/0000-0002-0817-1627)
- E. Gabandé-Rodríguez
- Gabriel Núñez (ORCID: https://orcid.org/0000-0002-6529-2695)
- J. Poulton
- Isaac Francos-Quijorna (ORCID: https://orcid.org/0000-0003-2514-4206)
- José Ignacio Escrig-Larena (ORCID: https://orcid.org/0000-0002-1538-8808)
- Naohiro Inohara (ORCID: https://orcid.org/0000-0002-4215-9349)
- Juan Aranda (ORCID: https://orcid.org/0000-0002-5598-2465)
- Sandra Delgado-Pulido (ORCID: https://orcid.org/0000-0003-2055-6594)
- Pablo Ramírez-Ruiz de Erenchun
- Álvaro Fernández-Almeida (ORCID: https://orcid.org/0009-0006-1483-4585)
- Jorge Oller
- María Mittelbrunn
- Violeta Enriquez-Zarralanga
- José Antonio Enríquez
- Ana Victoria Lechuga-Vieco
- Raquel Justo-Méndez
- Manuel M. Gómez de las Heras
- Inés Berenguer-López
Institutions
- Universidad Complutense de Madrid (ES)
- Nuffield Health (GB)
- Centro de Investigación Biomédica en Red (ES)
- Michigan Center for Translational Pathology (US)
- Institute for Research in Biomedicine (ES)
- Instituto Ramón y Cajal de Investigación Sanitaria (ES)
- Hospital Universitario Fundación Jiménez Díaz (ES)
- Spanish National Centre for Cardiovascular Research (ES)
- Instituto de Investigación en Ciencias de la Alimentación (ES)
- Centro de Biología Molecular Severo Ochoa (ES)
- Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (ES)
- Universidad Autónoma de Madrid (ES)
- The University of Osaka (JP)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2026-01-14
- DOI
- https://doi.org/10.64898/2026.01.13.699287
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Comunidad de Madrid
- Ministerio de Ciencia, Innovación y Universidades
- Centro de Biología Molecular Severo Ochoa
- Universidad Autónoma de Madrid
- Ministerio de Ciencia e Innovación
- National Institutes of Health