mtDNA damage, Innate Immunity and Systemic Inflammation– MitoImmun

• Applicant: Professor David Pla Martin, Ph.D.
• Subject Area: Biogerontology and Geriatric Medicine ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574936596

Mitochondria are integral organelles required for normal cellular function and energy production. Reminiscent of their evolutionary origin, mitochondria contain their DNA (mtDNA), encoding crucial proteins for Oxidative Phosphorylation (OxPhos). The accumulation over time of mutations and burden in the mitochondrial genome (ΔmtDNA) is a common process that occurs in many tissues as one of the hallmarks of aging. mtDNA damage is generally caused by normal cellular function, affecting the integrity of the mitochondrial genome and influencing tissue homeostasis. The classical vision for the downstream effects of mtDNA damage is based on the impairment of energy production. Recent research highlights mitochondria's role in the regulation of innate immunity and has placed mtDNA at the center of immune control. Due to its similarity to the bacterial genome, when located outside the mitochondrial network, mtDNA is recognized by immune sensors. mtDNA leakage is observed as a response to cellular injury, triggering the activation of a specific immune response. Hence, it has been proposed that the progressive accumulation of cellular damage and reduction in the activity of clearance mechanisms, both hallmarks of aging, initiate a systemic inflammatory state contributing to tissue impairment. The goal of this proposal is to decipher if the natural acquisition of mtDNA alterations in the liver is linked to the activation of a systemic inflammatory response, and how this affects the integrity of secondary tissues. We will study the contribution of the liver to generate and amplify an immune response leading to a systemic reaction. In addition, we aim to study the contribution of autophagy to the downstream cellular response to mitochondrial oxidative damage, using an optogenetic approach and liver organoids. Understanding this relationship is crucial for comprehending age-related syndromes and potential interventions.

• DFG Programme: Research Grants