Cardiomyocyte-intrinsic somatic mtDNA mutations induce an OXPHOS-dependent immune response and promote progressive heart failure
Mitochondrial DNA (mtDNA) mutations accumulate with age, but their mechanistic contribution to aging remains unclear. The classical mtDNA mutator mouse expresses a proofreading-deficient mtDNA polymerase (POLG D257A ) and accumulates mtDNA mutations across all tissues leading to premature aging. However, this model cannot resolve whether the aging phenotype results from systemic dysfunction or cell-intrinsic effects of somatic mtDNA mutations. To overcome this limitation, we generated Polg iMut mice allowing spatial and temporal control of POLG D257A expression. We demonstrate here that mtDNA mutations induced in cardiomyocytes cause progressive contractile dysfunction and respiratory chain deficiency in the heart without accompanying systemic pathology. Proteomic analyses link cardiac mosaic respiratory chain dysfunction to a progressive immune response, characterized by up-regulation of antigen-processing proteins and immune cell infiltration. In contrast, longevity-associated pathways are suppressed and uncoupled from mitochondrial and immune alterations, indicating distinct regulatory mechanisms. These findings demonstrate that mtDNA mutations can drive cardiac dysfunction and reveal a mechanistic link between mitochondrial dysfunction, immune responses, and aging.
Authors
- Jelena Misic (ORCID: https://orcid.org/0000-0002-1562-0582)
- Patrick Giavalisco (ORCID: https://orcid.org/0000-0002-4636-1827)
- Florian A. Rosenberger (ORCID: https://orcid.org/0000-0003-4604-6170)
- Roberta Filograna (ORCID: https://orcid.org/0000-0002-6581-9426)
- Camilla Koolmeister (ORCID: https://orcid.org/0000-0002-4052-3442)
- David Alsina (ORCID: https://orcid.org/0000-0003-0708-7391)
- Nils‐Göran Larsson (ORCID: https://orcid.org/0000-0001-5100-996X)
- Anna Wredenberg (ORCID: https://orcid.org/0000-0002-2500-6121)
- Polyxeni Papadea (ORCID: https://orcid.org/0000-0002-5131-8196)
- Diana Rubalcava-Gracia (ORCID: https://orcid.org/0000-0002-4615-7375)
- Kristina Bubb (ORCID: https://orcid.org/0000-0002-8457-0566)
- Daniel Andersson (ORCID: https://orcid.org/0000-0003-4548-702X)
- Giovanni Rigoni (ORCID: https://orcid.org/0009-0004-0476-9105)
- Gianluigi Pironti (ORCID: https://orcid.org/0000-0001-9401-3029)
- Shan Jiang (ORCID: https://orcid.org/0000-0003-2020-6447)
- Matthias Mann (ORCID: https://orcid.org/0000-0003-1292-4799)
Institutions
- Karolinska University Hospital (SE)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Max Planck Institute of Biochemistry (DE)
- Max Planck Institute for Biology of Ageing (DE)
- Technical University of Munich (DE)
- Universidad Nacional Autónoma de México (MX)
Publication Details
- Journal
- Science Advances
- Published
- 2026-09-04
- DOI
- https://doi.org/10.1126/sciadv.aec8606
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Stiftelsen Promobilia
- Petrus och Augusta Hedlunds Stiftelse
- Deutsche Forschungsgemeinschaft
- Cancerfonden
- Hjärnfonden
- Hjärt-Lungfonden
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- Åhlén-stiftelsen
- Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse
- Reumatikerförbundet
- Svenska Diabetesstiftelsen
- Novo Nordisk Foundation Center for Basic Metabolic Research
- Dirección General de Asuntos del Personal Académico, Universidad Nacional Autónoma de México
- HORIZON EUROPE European Research Council