Spatial and temporal impact of mtDNA mutations on aging

• Applicant: Dr. Kristina Bubb
• Subject Area: Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567141082

Somatic mitochondrial DNA (mtDNA) mutations are common in human tissues and accumulate with age, yet their direct contribution to aging and age-related diseases remains unclear. The widely cited mtDNA mutator mouse model has demonstrated that a high burden of mtDNA mutations can cause premature aging. However, it has key limitations: mutations occur in all cell types, making it difficult to distinguish tissue-specific effects, and developmental consequences cannot be separated from adult-onset mutations. These limitations hinder our ability to determine how and when mtDNA mutations drive aging and disease. To overcome these challenges, we will employ a novel inducible, tissue-specific mtDNA mutator mouse model (PolgiMut/PolgiMut) that enables Cre-recombinase-mediated activation of the mtDNA mutator allele in selected cell types at defined time points. We hypothesize that mtDNA mutations in hematopoietic cells and the liver drive systemic aging by inducing chronic low-grade inflammation ("inflammaging") and metabolic dysfunction. Furthermore, we propose that postnatal mtDNA mutations lead to neoantigen formation, triggering an immune response that accelerates aging. The primary aim of this proposal is to determine the spatial and temporal impact of mtDNA mutations on aging. To achieve this, we will employ our novel inducible mtDNA mutator model alongside genetic, histological, biochemical, and molecular techniques. First, we will investigate whether mtDNA mutations in hematopoietic cells impair function, alter lineage distributions, and drive systemic inflammation, contributing to premature aging. Second, we will determine how mtDNA mutations in hepatocytes affect mitochondrial function, metabolic profiles, and inflammatory markers to understand their role in aging-related dysfunction. Finally, we will examine whether postnatal induction of mtDNA mutations leads to neoantigen formation, triggering immune activation and metabolic decline. Additionally, we will compare the effects of embryonic versus adult-onset mtDNA mutations on hepatic metabolism, inflammation, and systemic aging. This tissue-specific inducible mtDNA mutator model represents a paradigm shift in aging research, allowing us to pinpoint the contributions of somatic mtDNA mutations in a controlled, time- and tissue-specific manner. Our findings will provide unprecedented mechanistic insights into how mtDNA mutations drive systemic aging and inflammation. By identifying key pathways linking mitochondrial dysfunction to age-related decline, this work has the potential to inform novel therapeutic strategies to mitigate aging and extend healthspan.

• DFG Programme: Fellowship
• International Connection: Sweden
• Host: Professor Nils-Göran Larsson, Ph.D.